MX2009001155A - Caspase inhibitors based on pyridazinone scaffold. - Google Patents

Abstract

The present invention relates to a pyridazinone derivative which can be used as a caspase inhibitor, process for the preparation thereof, and pharmaceutical composition for inhibiting caspase comprising the same.

Description

CASPASA INHIBITORS BASED ON THE PYRIDAZINONE STRUCTURE i TECHNICAL FIELD The present invention relates to a pyridazinone derivative or pharmaceutically acceptable salt thereof as an inhibitor against several caspases including caspase-1 I [enzyme converting interleukin-13, ICE], caspase-3 [apopain / CPP-32], caspase-8 and caspase-9, and a pharmaceutical composition for the inhibition of caspase comprising the same. BACKGROUND TECHNIQUE Caspase is a new class of cistern protease in the tetramer form a2 / ¾ discovered during the last 10 years. Around 14 classes of them have been known so far. Caspase-1 (ICE), one of them, is a class of citokokine and is involved in converting prointerleucine-1? biologically inactive to interleukin-1 /? active Interleukin-1 consists of interleukin-la and interleukin-1 / S, both of which are synthesized in monocytes in the form i of the 31KDa prucursor. Only the prointerleucina-? is activated by ICE. The positions hydrolyzed by caspase-1 are Asp2-Gly28 and Asp116-Ala117. The hydrolysis of the last position gives interleukin-l ?. Interleukin-1? it has been reported to act as an important mediator in causing inflammation (1,3). Caspase-1 has been discovered by The first time in 1989, and the three-dimensional structure of it was determined by the crystallographic method of rays by two independent study groups. 1 Caspase-3 (CPP-32) is widely studied for its function or mechanism of action, and its three-dimensional structure was determined in 1996 (2). Activated caspase-3 (apopain) of procaspase-3 is hydrolyzed at the position of the (P4) Asp-XX-Asp (Pj.) Portion, and known substrates include poly (DP-ribose) polymerase, small nuclear ribonucleoprotein Ul of 70,000 Mr, catalytic subunit of DNA dependent protein kinase of 460,000 Mr, etc. The X-ray structure of caspase-7 has been reported to be very similar to that of caspase-3 (). Caspases-8 and 9 occur upstream of caspase-3, 6, 7, and all these caspases are known to participate in the apoptosis cascade. The X-ray structure of caspase-8 was determined in 1999 (5), and particularly the inhibitors thereof can be advantageously used to treat diseases related to apoptosis. Caspase inhibitors mean those compounds that inhibit the activity of caspase, and to control such symptoms as inflammation, apoptosis, etc.

I caused by the activity of caspase. Diseases or symptoms that can be treated or mitigated when administering the i I inhibitors include the following: dementia, stroke, brain deterioration due to AIDS, diabetes, ulcer; gastric, brain injury due to hepatitis virus, hepatic diseases induced by hepatitis, acute hepatitis, fulminant hepatic failure, sepsis, organ transplant rejection, rheumatic arthritis, ischemic heart disease and cirrhosis of the liver (6). Among the caspase inhibitors known up to now, the most noticeable irreversible inhibitors are the following: IDN-1965 MX-1013 Both of the above inhibitors exhibit their activity based on the common mechanism of irreversibly inactivating the enzyme to suppress cellular apoptosis! (broad spectrum inhibitor, irreversible). It has been reported that the irreversible inhibitor has much more effective inhibitory activity than the reversible inhibitor (7). Both IDUN-1965 from IDUN Co. and MX-1013 from Maxim Co. are reported to show activity in the cellular apoptosis model for liver injury (8, 9). These compounds are now in the preclinical testing stage. The irreversible inhibitor IDN-6556 is now in the Phase II clinical trial stage as a therapeutic agent for the injury hepatic (10, 11).

References: (1) Inflammation: Basic Principles and Clinical Correlates, 2nd edition, ed by Gallin, Goldstein and Snyderman. Raven Press Ltd., New York. 1992, pages 211-232; Blood, 1996, 87 (6), 2095-2147. ! (2) Wilson, K. P. et al., Nature, 1994, 370. 2; 70; Alker, N. P. C. et al., Cell, 1994, 78, 343; Nature Structural Biology, 1996, 3 (7), 619. j (3) Thomberry, N. A. et al., Nature, 1992, 356. 768; Nature Biotechnology, 1996, 14, 297; Protein Science, 1995, 4, 3; Nature, 1995, 376 (July 6), 37; Proteih Science, 1995, 4, 2149. (4) ei, Y. et al., Chemistry and Biology, 2000, 7, 423. (5) Blanchard H. et al., Structure, 1999, i 7, 112; 5; Blanchard H. et al., J. of Mol. Biol., 2000, 302, 9. (6) References for diseases related to caspase I Dementia: Arch Neurol 2003 March; 60 (3): 369-76, Caspasé gene expression in the brain as a function of the clinic ^ l progression of Alzheimer's disease. Pompl PN, Yemul S, Xiang Z, Ho L, Haroutunian V, Purohit D, Mohs R, Pasinetti GM. Cerebral Stroke: Proc Nati Acad Sci USA November 12, 2002; 99 (23): 15188-93, Caspase activation and neuroprotection in caspase-3-deficient mice after in vivo cerebral ischemia and in vitro oxygen glucose deprivation. He gives, u, and, Huang Z, Matsushita K, Plesnila N, Augustinack JC, Hyman feT, Yuan J, Kuida K, Flavell RA, Moskowitz MA. j Deterioration of the brain due to AIDS: J Neurosci 15 de Ma ^ o del 2002; 22 (10): 4015-24, Caspase cascades in human immunoeficiency virus-associated neurodegeneration. Garden GA, Budd SL, Tsai E, Hanson L, Kaul M, D 'Emilia D, Friedlander RM, Yuan J, Masliah E, Lipton SA. Diabetes: Diabetes June 2002; 51 (6): 1938-48, Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway. Cai L, Li, Ang G, Guo L, Jiang Y, Kang YJ. Gastric ulcer: J Physiol Pharmacol December 1998/49 (4): 89-500, Role of basic fibroblast growth factor in the su'ppression of apoptotic caspase-3 during chronic gastric ulcer healing. Slomiany BL, Piotrowski J, Slomiany A.! Brain injury due to the hepatitis virus: J Viral Hepat I March 2003; 10 (2): 81-6, Cerebral dysfunction in chronic hepatitis C infection. Forton DM, Taylor-Robinson SD, Thomas HC. Fulminant hepatic failure: Gastroenterology August 2Qj00; 119 (2): 446-60, Tumor necrosis factor alpha in the pathogenesis of human and murine fulminant hepatic failure. Streetfc K, Leifeld L, Grundmann D, Ramakers J, Eckert K, Spengler U, Brenner D, Manns M, Trautwein C. Sepsis: Nat Immunol December 2000; 1 (6): 496-501, Caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte. Hotchkiss RS, Chang KC, I Swanson PE, Tinsley K, Hui JJ, Klender P, Xanthoudakis S, Roy S, Black C, Grimm E, Aspiotis R, Han Y, Nicholson D, Karl IE. I Rejection of organ transplantation: I Xenotransplantation May 2001; 8 (2): 115-2, In vitro prevention of cell-mediated xeno-graft rejection via the Fas / FafeL-path and in CrmA-transducted porcine kidney cells. Fujino M, Li XK, Suda T, Hashimoto M, Okabe K, Yaginuma H, Mikoshiba K, Guo L, Okuyama T, Enosawa S, Amemiya H, Amano T, Suzuki S. i! Rheumatic arthritis: Prog Med Chem 2002; 39: 1-72, Caspasé inhibitors as anti-inflammatory and antiapoptotic agents. Graczyk PP. Ischemic cardiac diseases: Am J Physiol Heart j Circ Physiol September 2002; 283 (3): H990-5, Hypoxiá-induced cleavage of caspase-3 and DFF45 / ICAD in human failed cardiomyocytes. Todor A, Sharov VG, Tanhehco EJ, i Silverman N, Bernabei A, Sabbah HN. 'Anti-inflammation: J Immunol March 15, I 2003; 170 (6): 3386-91, A broad-spectrum caspase inhibitor attenutes the allergic airway inflammation in murine asthma model. Iwata A, Nishio K, Winn RK, Chi EY, Henderson WR Jr, would make 1 JM. Hepatic diseases induced by hepatitis: i) J Viral Hepat. September 2003; 10 (5): 335-42. Apoptosis in hepatitis C Kountouras J, Zavos C, Chatzopoulos D.; ii) Apoptosis. December 2003; 8 (6): 655-63. Apoptosis participates to liver damage in HSV-induced fulminant hepatitis. Pretet JL, Pelletier L, Bernard B, Coumes-Marquet i S, Kantelip B, Mougin C; iii) Proc Nati Acad Sci E U A. 2003 and June 24; 100 (13): 7797-802. Caspase 8 small interfering RNA prevente acute liver failure in mice. Zender L, Hutker S, Liedtke! C, Tillmann HL, Zender S, Mundt B, Waltemathe M, Gosling1 T, Flemming P, Malek NP, Trautwein C, Manns MP, I Kuhnel F, Kubicka S. Cirrhosis of the liver: i) J Pharmacol Exp Ther. March 20 | 04; 308 (3): 1191-6, The caspase inhibitor Idn-6556 attenuates hepatic injury and fibrosis in the bile duct ligated 'mouse. Canbay A., Fledstein A., Baskin-Bey E., Bronk FS. Gorés GJ .; ii) Hepatology. February 2004; 39 (2): 273-8, i Apoptosis: the nexus of liver injury and fibrosis. Canbay A, Friedman S, Gores GJ.; iii) Hepatology. November of 2003; 3B (5): 1188-98, Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression.

Canbay A, Feldstein AE, Higuchi H, Werneburg N, Grambihler A, i Bronk SF, Gores GJ. (7) u J. et al. Methods:? Companion to Methods in Enzymology, 1999, 17, 320. (8) Hoglen NC et al., J. of Pharmacology and Experimental Therapeutics, 2001, 237, 811. (9) Jaeschke H. et al., Toxicology and Applied Pharmacology, 2000, 169, 11. (10) Hoglen NC and collaborators, J. Pharmacol Exp. Ther. , J 2004, 309 (2): 634. Characterization of IDN-6556 (3- [2- (2-tert-butyl-phenylaminooxalyl) -amino] -propionylamino] -4-oxo-5- (2, 3 5, 6-tetrafiuoro-phenoxy) -pentanoic acid): a liver-targeted caspase inhibitor. (11) Canbay? et al., J. Pharmacol Exp. i Ther., '2004, 308 (3), 1191. The caspase inhibitor IDN-6556 attenuStes hepatic injury and fibrosis in the bile duct ligateii mouse. DETAILED DESCRIPTION OF THE INVENTION [Technical Objective] The present inventors have extensively studied designing novel compounds that can be used as an effective and more selective inhibitor against caspases.

[Means for Resolving the Target] To achieve this goal, the present inventors synthesized several compounds, and determined their binding ability and inhibitory activity for caspases. As a result, the inventors have discovered that a compound of the following formula (1) fulfills such requirements and completed the present invention. [Formula 1] in which R, R1, R2, R3, R5, R6, R7 and X are as defined below. Therefore, the present invention provides the novel pyridazinone derivative of the formula (1) or pharmaceutically acceptable salt thereof having effective inhibitory activity against caspases. ! It is another object of the present invention to provide a pharmaceutical composition for inhibiting caspase, specifically a composition for preventing inflammation and apoptosis, comprising the compound of formula (1) or pharmaceutically acceptable salt thereof as an active ingredient together with the carrier pharmaceutically acceptable.

[Advantageous Effect] The compound of the formula (I) according to the present invention has an excellent inhibitory activity against caspase, and in this way it can be advantageously used for the treatment of various diseases and symptoms mediated by caspase. [Best Mode for Carrying Out the Invention] First of all, important terms in the present invention are defined as follows: a) C1-C5 alkyl: straight or branched chain hydrocarbons having 1 to 5 carbon atoms, which they include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butylol, etc., but are not limited thereto. b) C3-C10 cycloalkyl: Cyclic hydrocarbons having 3 to 10 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., but are not limited thereto. c) Aryl: Aryl group includes all aromatics, heteroaromatics and their partially reduced derivatives. The aromatic group means an unsaturated hydrocarbon of 5 to 15 members alone or fused. The heteroaromatic group means an aromatic group containing 1 to 5 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen. The aryl group includes phenyl, naphthyl, indolyl, quinolinyl, isoquinolyl, imidazolinyl, isoxazolyl, oxazolyl, thiazolyl, etc., but is not limited thereto. One or more hydrogens in the C1-C5 alkyl group, cycloalkyl -C10 alkyl or aryl can be replaced with a group (s) selected from the following: acyl, amino, carbamoxy, carboxy, carboxyamino, cyano, halo group , hydroxy, nitro,; uncle, alkyl, cycloalkyl, alkoxy, aryl, aryloxy, sulfoxy and guanido. d) Natural amino acids include the following: Glycine, Alanine, Valine, Leucine, Isoleucine, Serine, Threonine, Cysteine, Methionine, Proline, Aspartic Acid, Asparagin, Glutamic Acid, Glutamine, Lysine, Arginine, Histidine, Phenylalanine, Tyrosine and Tryptophan. In addition, the present specification includes the following abbreviations: 'N-bromosuccinimide: NBS O- (7-azabenzotriazol-1-yl) -N,, N', N '-tetramethyl-uronium hexafluorophosphate]: HATU N, -dimethyl formamide: DMF Dimethyl sulfoxide: DMSO N-methylmorpholine: NMM 2, 2 '-Azobis (2-methyl propionitrile): AI BN 1 2, 2, 6, 6-Tetramethyl-l-piperidinyloxy, free radical: TEMPO lithium bis (trimethylsilyl) amide: LiHMDS 'N- (2-Hydroxyethyl) piperazine-N' - (2'-ethanesulphonic acid) phonic]: HEPES I i i 3- [(3-Colamidopropyl) dimethylamino] -1-propanesul-fonatoi: CHAPS Ethylenediaminetetraacetic acid: EDTA Dithiothreitol: DTT The present invention will be explained in more detail below. One aspect of the present invention relates to the pyridazinone derivative of the following formula (1): [Formula 1] wherein I) R1 represents H, Ci-C5 alkyl, C3-C10 cycloalkyl, aryl, or a side chain residue of all natural amino acids, II) R2 represents H, C1-C5 alkyl, C3-C 10 cycloalkyl, aryl, or a side chain residue of all natural amino acids, III) R3 represents C1, C 1 -C 5 alkyl, hydroxy, C 1 -C 5 alkoxy or halogen, IV) R 4 represents H , C 1 -C 5 alkyl, C 3 -C 3 0 cycloalkyl or aryl, V) R 5 represents H, C 1 -C 5 alkyl, C 3 -C 10 cycloalkyl or aryl, VI) R6 and R7 independently of each other represent H, C 1 -C 5 alkyl, C 3 -C 10 cycloalkyl or aryl, VII) X represents -CH 2 OR 9 (R 9 is C 1 -C 5 alkyl, C 3 -C 10 cycloalkyl or aryl ), -CH2OC (0) R10 (R10 is C1-C5 alkyl, C3-C10 cycloalkyl or aryl), -CH2-0P (= 0) Ru2 (R11 is C1-C5 alkylp, C3-C10 cycloalkyl) or aryl), or -CH2-W (W is halogen), or pharmaceutically acceptable salt thereof, which is useful as an inhibitor for caspase. In the compound of formula (1) according to the present invention, R1 preferably represents a side chain residue of all natural amino acids, more preferably -CH2C00H. The compound of the formula (1) can include the two kinds of stereoisomers, or mixtures thereof (diastereomeric mixtures) when the carbon to which R1 is urided becomes a stereocenter due to the group R1. The compound of the formula (1) can include an ester form (-C02Y wherein Y is C1-C5 alkyl), a sulfonated form (-C0NHS02Z wherein Z is C1-C5 alkyl), and a form of pharmaceutically acceptable salt, when R1 is an amino acid side chain residue containing the carboxyl moiety; or the compound of the formula (1) can also exist in the form of a pharmaceutically acceptable salt when R1 is a side chain residue of an amino acid containing a base portion. The compound of the present invention (formula la) it can exist in the form of a cyclic ketal (formula Ib) when R1 is -CH2COOH, and thus a skilled person can understand that the cyclic ketal form (formula Ib) can also be converted by the present invention.

Formula l to Formula I b I Also, the equilibrium forms of the compounds must be understood to cover their tautomorphous forms.; R2 preferably represents C1-C5 alkyl, more preferably methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. The compound of the formula (1) can include two kinds of stereoisomers, or mixtures thereof (diastereomeric mixtures) when the carbon to which R2 is attached becomes a stereocenter due to the group R2. The compound of the formula (1) can include an ester form (-CO2Y wherein Y is C1-C5 alkyl), a sulfonamide form (-CON HS02Z wherein Z is C1-C5 alkyl) and a of pharmaceutically acceptable salt, when R2 is a residue} side chain of an amino acid containing the carboxyl portion; or the compound of the formula (1) may also exist in the form of a pharmaceutically acceptable salt when R2 is a side chain residue of a amino acid that contains a base portion. R 3 preferably represents H, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, or halogen, more preferably H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl, methoxy ethoxy, fluoro or chloro. R4 preferably represents H. R5 preferably represents C1-C5 alkyl substituted by substituted or unsubstituted C3-C10 cycloalkyl or substituted or unsubstituted aryl; or represents substituted or unsubstituted aryl. R5 more preferably represents C1-C5 alkyl substituted by 1 C3-C10 cycloalkyl which is unsubstituted or substituted by or more substituents selected from the group consisting of C1-C5 alkyl, hydroxy, C1-C5 alkoxy and halogen, or by aryl which is unsubstituted or substituted by one or more substituents selected from the group consisting of C1-C5 alkyl, hydroxy, C1-C5 alkoxy and halogen; or represents aryl which is unsubstituted or substituted by one or more substituents selected from the group consisting of C 1 -C 5 alkyl, hydroxy, C 1 -C 5 alkoxy and halogen. For example, R 5 i is feriyl, naphthyl, indolyl, quinolinyl, isoquinolyl, imidazolinyl, isoxazolyl, oxazolyl or thiazolyl, or is methyl substituted by phenyl, naphthyl, indolyl, quinolinyl, isoquinolyl, imidazolinyl, isoxazolyl, oxazolyl, thiazolyl or cyclohexyl, each of which is not substituted or substituted by one or more substituents selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, trihalomethyl and halogen. R6 and R7 each preferably represents H. R9 preferably represents aryl substituted by one or more halogens, more preferably phenyl substituted by one or more fluorines and much more preferably 2,3,5,6-tetrafluorophenyl, 2, 3 , 6-trifluorophenyl or 2,6-difluorophenyl. R10 preferably represents aryl substituted by one or more halogens, more preferably phenyl substituted by one or more chlorines, much more preferably 2,6-dichlorophenyl. R11 preferably represents aryl, more preferably phenyl. preferably represents F. The much more preferred compounds are those selected from the following group: 5-Fluoro-3- [2- (5-methyl-3-oxo-2-phenyl-2,3-dihydro-pyridazin-4) il) -butyrylamino] - -oxo-pentanoic acid (1); 3- [2- (2-Benzyl-5-methy1-3-OXO-2, 3-dihydro-pyridazin-4-yl) -butyrylamino] -5-fluoro-4-oxo-pentanoic acid (2); j 3- [2- (2-Benzyl-3-oxo-2,3-dihydro-pyridazin-4-yl) -butyrylamino] -5-fluoro-4-oxo-pentanoic acid (3); '3- [2- (2-Benzyl-5-chloro-3-oxo-2,3-dihydro-) acid pyridin-4-yl) -butyrylamino] -5-fluoro-4-oxo-pentanoic acid (4); 3- [2- (2-Benzyl-5-methoxy-3-oxo-2,3-dihydro-pyridaz: in-4-yl) -butyrylamino] -5-fluoro-4-oxo-pentanoic acid (5); 3-2- [2- (2-tert-Butyl-benzyl) -3-oxo-2,3-dihydrp-pyridazin-4-yl] -butyrylamino-5-fluoro-4-oxo-pentanoic acid (6); 3-2- [2- (3-tert-Butyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyrylamino-5-fluoro-4-oxo-pentanoic acid (7); 5-Fluoro-3-2- [2- (2-methyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyrylamino-4-oxo-pentanoic acid (8); 5-Fluoro-3-2- [2- (3-methyl-benzyl) -3-oxo-2,3-dihydrc-pyridazin-4-yl] -butyrylamino-4-oxo-pentanoic acid (9); 5-Fluoro-3-2- [2- (3-methoxy-benzyl) -3-oxo-2,3-dihydrp-pyridazin-yl] -butyrylamino-4-oxo-pentanoic acid 10); 5-Fluoro-3- [2- (2-naphthalen-l-ylmethyl-3 - ?? - 2, 3-dihydro-pyridazin-4-yl) -butyrylamino] - -oxo-pentanoic acid (eleven); 5-Fluoro-3- [2- (2-naphthalen-2-ylmethyl-3 - ?? - 2, 3-dihydro-pyridazin-4-yl) -butyrylamino] -4-oxo-pentanoic acid (12); 5-Fluoro-3-2- [2- (2-methyl-oxazol-4-ylmethyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -buyrylamino- -oxo-pentanoic acid (13);; ! 5-Fluoro-3-2- [2- (2-methyl-thiazol-4-ylmethyl) -3- acid B-dihydro-pyrida zin- -i1] -butyrylamino-4 -oxo-pentanoic acid (14) 3-2- [2- (3, 5-Dimethyl-isoxazol-4-ylmethyl) -3-oxo-2, 3-dihydro-pyridazin-4-yl] -butyrylamino-5-fluoro-4 acid ??? - pentanpico (15); 3- [2- (2-Cyclohexylmethyl-3-oxo-2,3-dihydro-pyrida ^ in-4-yl) -butyrylamino] -5-fluoro-4-oxo-pentanoic acid (16); 5-Fluoro-3- [2- (2-isoquinolin-1-ylmethyl-3-oxo-2,3-diljido-4-pyridazin-4-yl) -butyrylamino] -oxo-pentanoic acid (17); Acid 3-. { 2- [2- (2-chloro-benzyl) -3-oxo-2,3-dihydro-pyridin-4-yl] -but-irylamino} -5-fluoro--oxo-pentanoic (18); Acid 3-. { 2- [2- (3-Chloro-benzyl) -3-oxo-2,3-dihydro-pyridin-4-yl] -butyrylamino} -5-fluoro-4 -oxo-pentanoic (19); Acid 3-. { 2- [2- (3-Bromo-benzyl) -3-oxo-2,3-dihydro-pyridin-4-yl] -butyrylamino} -5-fluoro-4 -oxo-pentanoic (20); ! 5-fluoro-4-oxo-3- acid. { 2- [3 - ??? - 2- (2-trifluoro-methyl-benzyl) -2, 3-dihydro-pyridazin-yl] -butyrylamino} pentanoic (21); 5-fluo or-4-oxo-3 acid. { 2- [3-Oxo-2- (3-trifluoromethyl-benzyl) -2, 3-dihydro-pyridazin-4-yl] -butyrylamino} pentanoic (22); ! Esther (S) -3-. { (R) -2 - [2 - (2-1-buty-1-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyrylamino} -4-carboxy-2 - ??? - butylide of 2,6-dichlorobenzoic acid and ester (S) -3-. { (S) -2- [2- (2-tert-Butyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyriamino} -4-carboxy-2-oxo-butylic acid 2,6-dichloro-benzoite (23-1, 23-2); Acid (S) -3-. { (R) -2- [2- (2-tert-Butyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyrylamino} -4-oxo-5- (2, 3, 5, 6-tetrafluoro-phenoxy) -pentanoic acid and (S) -3-. { (S) -2- [2- (2-tert-buyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyrylamino} -4 -oxo-5- (2, 3, 5, 6-tetrafluoro-phenoxy) -pentanoic acid (24-1, 24-2); 1 Acid (S) -3-. { (R) -2- [2- (3-tert-Butyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyriamino} -4 -oxo-5- (2, 3, 5, 6 -tetrafluoro-phenoxy) -pentanoic acid and (S) -3-. { (S) -2- [2- (3-tert-butyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-yl] -butyrylamino} -4-OXO-5- (2, 3, 5, 6-tetrafluoro-phenoxy) -pentanoic acid (25-1, 25-2); Acid (S) -3-. { (R) -2- [2- (2-tert-Butyl-benzyl) -3-oxo-2,3-di-idro-pyridazin-4-yl] -butyl-amino} - -oxo-5- (2,3,6-trifluoro-phenoxy) -pentanoic acid and (S) -3-. { (S) -2- [2- (2-tert-Butyl-benzyl) -3-oxo-2,3-dih! Idro-pyridazin-4-yl] -butyryl-amino} -4-oxo-5- (2,3,6-trifluoro-phenoxy) -pentanoic acid (26-1, 26-2); Acid (S) -3-. { (R) -2- [2- (2-tert-Butyl-benzyl) -3-oxo-2,3-dih) idro-pyridazin-4-yl] -butyrylamino} -5- (2,6-difluoro-phenoxy) -4- oxo-pentanoic acid and (S) -3-. { (S) -2- [2- (2-tert-butyl-benzyl) -3-oxo- 2, 3-di-idro-pyridazin-4-yl] -butyrylamino} -5- (2,6-difluoro-phenoxy) -4 -oxo-pentanoic acid (27-1, 27-2); and Acid (S) -3-. { 2- [2- (2-tert-Butyl-benzyl) -3-oxo-2,3-dihydrb-pyridazin-4-yl] -butyrylamino} -5- (diphenyl-phosphino-yloxy) -oxo-pentanoic acid (28). The processes for the preparation of the novel pyridazinone derivative of the formula (1) which shows an inhibitory activity against caspases are represented in the following Reaction Schemes 1 to 4. However, those illustrated in the following Reaction Schemes represent only the processes typical used in the present invention. The order of handling, reactive, reaction condition, solvent, etc. they can be changed without limit. [Reaction Scheme 1] In Reaction Scheme 1 above, an alkylaldehyde (2), for example propionaldehyde, and a secondary amine, for example diethylamine, are dehydrated in the presence of magnesium sulfate to give an enamine compound (3). This enamine (3) is reacted with a dialkylmaleate, for example dimethylmaleate, in a suitable solvent, for example methylene chloride and treated with acetic acid to give an aldehyde compound (4). Then, the aldehyde compound (4) and hydrazine hydrate are reacted in a suitable solvent, for example ethanol, to give a dihydropyridazinone compound (5). The dihydrctpyridazinone compound (5) is oxidized with a suitable oxidizing agent, for example thionyl chloride, in a suitable solvent, for example methylene chloride, to give the desired compound of the pyridachinone structure (6). [Reaction Scheme 2] or- 3 (2H) -pyridazinone (7) is protected by the methoxythnetyl protecting group (8), and reacted with diethyl malonate and sodium ethoxide to give a diethyl malonate derivative (9). The derivative (9) is heated with NaCl in DMSO to leave monoacetate (10). The monoacetate thus obtained (10) is treated with Pd / C under a hydrogen atmosphere to synthesize the derivative (11). This derivative (11) is deprotected to I use BBr3, and the resulting derivative (12) is reacted with a suitable alkyl halide to give the derivative (13). This derivative (13) is reacted with LiHMDS and a suitable alkyl halide to give the derivative (14), which is further hydrolyzed, if necessary, to give the carboxylic acid derivative (15) that does not have the protecting group. [Reaction Scheme 3] Dess-Martin In Reaction Schemes 3 and 4, Z represents -OR9 (&9 is C1-C5 alkyl, C3-C10 cycloalkyl or aryl), (R10 is C1-C5 alkyl, C3-C10 cycloalkyl or aryl) or -W (W is halogen). As represented in Reaction Scheme 3 above, the carboxylic acid derivative (15) is coupled with the aspartic acid derivative (18) (see Reaction Scheme I below) to give the compound (16) , which will then undergo the Dess-Martin peryodene oxidation reaction and the deprotection reaction, if necessary, to give the desired compound of the formula (1). The functional group Z in the compound (1) of the Reaction Scheme 3 can be formed first by synthesizing the compound (18) since it has the desired group Z according to the | process of Reaction Scheme 4, and by reacting the compound (18) with the carboxylic acid compound (15) (see WO 00/23421). Or, the group 1 Z desired Z can be entered after according to the process! from Reaction Scheme 4 then the carboxylic acid compound (15) is combined with the aspartic acid (? -t-Bu) ^ methyl ester and hydrolyzed. When Z is F, the racemic compound can be prepared according to a method known from Tetrahedron Letters, 1994, 35 (52), 9693-9696. [Reaction Scheme 4] O CbzNH NaBH. CbzNH The compound of formula (1) according to the present invention has a broad spectrum of inhibitory activity against caspases as demonstrated by the results of the following Experiments, and thus has an effect1 to prevent inflammation and apoptosis. Thus, the present invention provides a pharmaceutical composition for inhibiting caspases, specifically a therapeutic composition for preventing inflammation and apoptosis, comprising the compound of formula (1) or pharmaceutically acceptable salt thereof as an active ingredient i together with the carrier. pharmaceutically acceptable. Specifically, the composition of the present invention has a therapeutic or preventive effect for dementia, cerebral stroke, brain impairment due to AIDS, diabetes, gastric ulcer, brain injury due to hepatitis, liver diseases induced by hepatitis, acute hepatitis, fails fulminant hepatic, sepsis, rejection of I organ transplantation, rheumatic arthritis, cardiac cell apoptosis due to ischemic heart disease or cirrhosis of the liver. The compound of the formula (1) can be formulated in various pharmaceutical forms for the purpose of administration. To prepare the pharmaceutical composition according to the present invention, an effective amount of the compound of the formula (1) or pharmaceutically acceptable salt of the same is mixed with a pharmaceutically acceptable carrier which can take a wide variety of j forms depending on the formulation that is prepared. The caspase inhibitor compound can be formulated as a parenteral injection, or percutaneous injection or oral preparation, depending on its purpose of application. It is especially advantageous to formulate the composition in a unit dosage form to facilitate administration and uniformity of dosage. For the oral preparation, any usual pharmaceutical carrier can be used. For example, water, glycols, oils, alcohols and the like can be used for such liquid oral preparations as suspensions, syrups, elixirs and solutions; or starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like can be used for such solid preparations as powders, pills, capsules and tablets Due to its easy administration, tablets and capsules are the much more advantageous unit dosage forms. It is also desirable that tablets and pills be formulated in the enteric coating preparation. For parenteral preparation, sterile water is usually used as the carrier, although other ingredients such as solubility aids can be used. Injections, for example, aqueous suspension or I sterilized oil for injection, can be prepared according to the known process using dispersion agent, wetting agent or suspending agent. Solvents that can be used to prepare injections include water, Ringer's fluid and isotonic NaCl solution and also sterilized fixed oil can be conveniently used as the solvent or suspension medium. Any non-stimulating fixed oil that includes mono- or di-glyceride can be used for this purpose. The fatty acid such as oleic acid can also be used for injections. For percutaneous administration, the carrier may include an agent that increases penetration and / or an agent! Suitable humectant, optionally combined with suitable additives that have no significant irritation to the skin. The additives may facilitate administration through: of the skin and / or may aid in the preparation of a desired composition. These percutaneous preparations are They are administered via various means, for example, as a transdermal patch, a specific stain or an ointment. I! When the caspase inhibitor of the present invention is used for the clinical purpose, it is preferable to administer to the subject patient in an amount ranging from 0.1 to 100 mg per kg of body weight a day. The total daily dosage can be administered once or for several times. However, the specific administration dosage for an individual patient may vary with the specific compound used, body weight, gender, hygienic condition, or diet of the subject patient), time or method of administration, rate of excretion, agent mixing ratio , severity of the disease that is treated, etc. [Modalities for Practicing the Invention] The present invention will be more specifically explained by the following examples. However, it should be understood that these examples are intended to illustrate the present invention but not in any way to limit the scope of the present invention. Preparation 1-1) Methyl ester of (5-methyl-3-oxo-2,3,4,5-tetrahydro-pyridazin-4-yl) -acetic acid magnesium sulfate (3.6 kg, 30.0 mol) introduced in diamylamine (6.6 kg, 90.0 mol), to which propiohaldehyde (1.76 kg, 30.3 mol) was added with maintenance of a temperature of 0 ° C. The mixture was warmed to room temperature, and stirred for 2.5 h. To this mixture was added 18 L of methylene chloride, which was then cooled to 0 ° C. Dimethylmaleate (3.04 kg, 21.1 mol) was added, and the resulting mixture was stirred for 20 h. The reaction mixture was filtered to remove the solid, and the filtrate was distilled under reduced pressure to give the dimethyl ester of 3-diethylamino-4-methyl-cyclobuole-1,2-dicarboxylic acid. The dimethyl ester of crude 3-diethylamino-methyl-cyclobutane-1,2-dicarboxylic acid obtained in the above was added tetrahydrofuran (10 L) and distilled water (5 L), acetic acid (2.54 kg, 42.3 mol) was added thereto and the mixture was stirred and stirred under reflux for 1 h. The tetrahydrofuran was removed by distillation under reduced pressure. Ethyl acetate was added to the residue, which was then extracted, dried, concentrated in a conventional manner to give the dimethyl ester of crude 2- (1-methyl-2-oxo-ethyl) succinic acid (3.44). kg). To this dimethyl ester of 2- (1-methyl-2-yl-ethyl) -syjcinic acid was added ethanol (13 L), which was cooled to 0 ° C. Acetic acid (1.2 kg, 20 mol) was added with maintenance of temperature. Hydrazine hydrate (1.08 kg, 21.6 mol) was added to the reaction mixture, which I warmed to room temperature and stirred for 16 h. Ethanol was removed by distillation under reduced pressure, methylene chloride was added to the residue, which was then extracted, dried, concentrated in a conventional manner to give the title compound (2.80 kg., Yield: 51%). i 'XH-NMR (CDCl 3, 500 MHz) d D 8.39 (br s, 1 H), 7.17 (d, 0. H), 6.94 (s, 0.5 H), 3.71 (d, 3 H), 3.20-3.15 (d. m, 0.5H), 3.03-2.98 (m, 0.5H), 2.78-2.73 (m, 1H), 2.67-2.61 (m, 1H), 2.39-2.34 (m, 0.5H), 1.24 (d, 0.5H), 1.01 (d, 1.5H) Preparation 1-2) Methyl ester of (5-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl) -acetic acid To the compound of Preparation 1- 1) (2.70 kg, 14.7 i mol) was added methylene chloride (27 L), which was then cooled to 0 ° C. Thionyl chloride (2.08 kg, 17.6 mol) was added thereto for 40 min. The mixture was warmed to room temperature and stirred for 4.5 h. To the mixture of In the reaction, 20 kg of 10% aqueous sodium chloride solution and 16 kg of methylene chloride were added. The organic layer obtained by phase separation was dried, concentrated in a conventional manner to give the title compound (1.72 kg, Yield: 64%) as a pale yellow solid. 1 H-NMR (CDCl 3, 500 Hz) d 12.08 (br s, 1H), 7.66 (s, 1H), 3.70 (s, 3H), 3.68 (s, 2H), 2.19 (s, 3H) Preparation 1-3) Methyl ester of acid (5-methyl-3-oxo-2-phenyl-2,3-dihydr -pyridazin-4-yl) -acetic To a mixture of the compound of Preparation 1-2) (182 mg, 1.0 mmol), phenylboronic acid (244 mg, 2.0 eq), Cu (OAc) 2-H20 (40 mg) was added. mg, 0.2 eq), pyridine (0.16 mL, 2.0 eq), ????? (172 mg, 1.1 eq) and molecular sieve (120 mg, 4A, powder, pre-dried) CH2C12 (10 mL), which was then stirred for 1 h at room temperature under nitrogen gas. The reaction mixture was exposed to air and stirred for one day. S $ added saturated ammonium acetate (30 mL) thereto and the mixture was extracted twice with ethyl acetate (100 mL). The extract was washed with dilute sodium hydrogen carbonate solution (NaHCO 3, 100 mL x 2), dried (Na 2 SO 4 anhydrcj ») and concentrated under reduced pressure. The residue was separated by column chromatography (20-35% ethyl acetate-hexane) to give 258 mg of the title compound in a stoichiometric yield. XH-NMR (500MHz, CDC13) d 7.75 (s, 1H), 7.58 (d, 2H), 7.44 (t, 2H), 7.36 (t, 1H), 3.70 (s, 3H), 3.68 (s, 2H) , 2.25 (s, 3H) 1 i i Preparation 1-4) I 2- (5-Methyl-3-oxo-2-phenyl-2,3-dihydro-pyridazin-4-yl) -butyric acid methyl ester The compound of Preparation 1-3) (258 mg, 1.0 mmol) was dissolved in anhydrous THF (10 mL) under nitrogen atmosphere and maintained at a temperature of -78 ° C. LiHMDS l.OM/THF (1.20 mL, 1.2 eq) was added thereto and the mixture was stirred for 10 min. Ethyl iodide (0.12 mL, 1.5 eq) was added and the mixture was heated slowly to room temperature, with stirring overnight. Water (20 mL) was added and the mixture was extracted with ethyl acetate (50 mL x 2), washed with aqueous sodium chloride solution! (100 mL), dried (a2SO4 anhydrous) and concentrated under reduced pressure to give 286 mg of the title compound in a stoichiometric yield. This compound was used in the next reaction without further purification. XH-NMR (500MHz, CDC13) d 7.72 (s, 1H), 7.60 (d, 2H), 7.44 (ti 2H), 7.35 (t, 1H), 3.77 (dd, 1H), 3.70 (s, 3H), 2.28 (m, 1H), 2.26 (s, 3H), 1.90 (ra, 1H), 0.92 (t, 3H) Preparation 1-5) I Acid 2- (5-methyl-3-oxo-2-phenyl-2 , 3-dihydro-pyridazin-4-yl) -butyric acid; The compound of Preparation 1-4) (286 mg) was dissolved in a solvent mixture (6 mL, tetrahydrofuran: MeOH: H20 = 3: 2: 1), LiOH.H20 (126 mg, 3.JO eq. ) thereto and the mixture was heated for about 2 h with stirring. The reaction solution was neutralized by 1N aqueous hydrochloric acid solution and it was broken under reduced pressure to remove tetrahydrofuran almost completely. The residue was dissolved in excess ethyl acetate (50 mL), washed with aqueous sodium chloride solution, dried (anhydrous Na 2 SO 4) and concentrated under reduced pressure to give the title compound) (272 mg) in a stoichiometric performance. This compound was used in the next reaction without further purification. Preparation 1-6) 5-Fluoro-3- [2- (5-methyl-3-oxo-2-phenyl-2,3-dihydro-pyridazin-4-yl) -butyrylamino] -4-tert-butyl ester -oxo-pentanoic I j A mixture of the carboxylic acid derivative of Preparation 1-5) (271 mg, 1.00 mmol), tert-butyl ester of j3-amino-5-fluoro-hydroxy-pentanoic acid (see Tetrahedron Letters , 1994, 35 (52), 9693-9696, 248 mg, 1.2 eq) and HATU (494 mg, 1.3 eq) was cooled to 0 ° C, triethylamine (0.56) was added.

I mL, 4.0 eq) thereto in D F solvent (5 mL) and the mixture was reacted for one day. The solvent was distilled under reduced pressure. The residue was extracted with ethyl acetate (30 mL x 2), washed with water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried (anhydrous Na 2 SO 4) and concentrated under reduced pressure. To this compound and the Dess-Martin reagent (848 mg, 2.0 eq1) was added anhydrous dichloromethane (4 mL), which then i was stirred for 1 h at room temperature. The reaction was stopped by isopropyl alcohol (1 mL). The solid was removed by celite filtration under reduced pressure and extracted with ethyl acetate (20 mL x 2). The extract was washed with water, saturated, saturated sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried (anhydrous Na 2 SO 4) and concentrated under reduced pressure. The residue was separated by column chromatography (30-40% ethyl acetate-hexane) to give 330 mg (72%) of the title compound. XH-NMR (500MHz, CDC13) d 7.79 (br m, 1H), 7.62 (m, 1H), 7;.50-7.25 (m, 5H), 5.20-4.80 (m, 2H), 4.80-4.68 (m , 1H), 3.75 (m, 1H), 2.88-2.57 (m, 2H), 2.26 (s, 3H), 2.26-1.98 (m, 2H), 1.41 (m, j 9H), 0.87 (m, 3H) Example 1) 5-Fluoro-3- [2- (5-methyl-3-oxo-2-phenyl-2,3-dihydro-pyridazin-4-yl) -butyrylamino] -4-oxo-pentanoic acid The compound of Preparation 1-6) (100 mg, 0.218 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (2 mL) was added at 0 ° C. The mixture was stirred for 1 h, during which time it was slowly heated to room temperature. The mixture was concentrated under reduced pressure and separated by column chromatography (10% methanol-dichloromethane) to give 68 mg (78%) of the title compound. XH-NMR (500MHz, DMSO-dg) d 7.93 (m, 1H), 7.84 (br s, I 1 H), 7.45-7.37 (m, 5H), 5.03 (m, 2H), 4.57-4.49 (m, 1H), 3.69 (m, 1H), 21.68-2.47 (m, 2H), 2.19 (s, 3H) ), 2.08-1.68 (m, 2H), 0.76 (m, 3H) j Mass M + H + 402.74 I Preparation 2-1) i Methyl ester of (2-benzyl-5-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl) -acetic acid To a mixture of compound of Preparation 1-2) (364 mg, 2.6 mmol) and CS2CO3 (977 mg, 1.5 eq) were added DMF (8 mL) and benzyl pyrid (0.31 mL, 1.3 eq), which was then stirred for 3 h 60 ° C under nitrogen atmosphere. The mixture was concentrated under reduced pressure and the residue was extracted twice with ethyl acetate (100 mL). The extract is washed < jj with saturated aqueous sodium hydrogen carbonate solution (NaHCO 3, 100 mL x 2) and aqueous sodium chloride solution, dried (anhydrous Na 2 SO 4) and concentrated under reduced pressure. The residue was separated by column chromatography ^ (30% ethyl acetate-hexane) to give 484 mg (89%) of the title compound. XH-NMR (500MHz, CDC13) d 7.61 (s, 1H), 7.39 (d, 2H), 7.35-7.'26 (m, 3H), 5.29 (s, 2H), 3.70 (s, 3H), 3.65 (s, 2H), 2.15 (s,! 3H) 1 Preparation 2-2) 2- (2-Benzyl-5-methyl-3-oxo-2,3-di'aidro-pyridazin-4-yl) -butyric acid methyl ester The compound of Preparation 2-1) ( 471 mg, 1.73 mmol) was dissolved in anhydrous THF (6 mL) under nitrogen atmosphere and maintained at -78 ° C. LiHMDS 1. OM / THF (2.10 mL, 1.2 eg) was added thereto and the mixture was stirred for 10 min. Ethyl iodide (0.21 mL, 1.5 eq) was added and the mixture was heated slowly to room temperature with stirring I during the night. The reaction was stopped by saturated ammonium acetate solution. The reaction mixture was extracted i with ethyl acetate (50 mL x 2), washed with aqueous sodium chloride solution (100 mL), dried (anhydrous Na 2 SO 4) and concentrated under reduced pressure. The residue was separated by column chromatography (20% ethyl acetate -helia) to give 400 mg (77%) of the title compound. 1H-NMR (500MHz, CDC13) d 7.57 (s, 1H), 7.37 (d, 2H), mmol) was dissolved in a solvent mixture (6 mL, tetrahydrofuran: MeOH: H20 = 3: 2: 1), LiOH.H20 (165 mg, 3.0 eq) was added thereto and the mixture was heated for about 2 h while stirring. The reaction mixture is neutralized by 1N aqueous hydrochloric acid solution, distilled under reduced pressure to remove tetrahydrofuran almost complex. The residue was dissolved in excess ethyl acetate (50 mL), washed with aqueous sodium chloride solution, dried (anhydrous Na 2 SO 4) and concentrated under reduced pressure to give 356 mg (100% Yield) of the title compound. Title. This compound was used in the Next reaction without further purification. Preparation 2-4) 3- [2- (2-Benzyl-5-methyl-3-OXO-2) tert-butyl ester, 3-dihydro-pyridazin-4-yl) -buyrylamino] -5-fluoro-4-oxo-peritanoic acid A mixture of the carboxylic acid derivative of Preparation 2-3) (153 mg, 0.535 mmol), ternary ester butyl of 3-amino-5-fluoro-4-hydroxy-pentanoic acid (see Tetrahedron Letterg, 1994, 35 (52), 9693-9696, 133 mg, 1.2 eq) and HATU (265 mg, 1.3 eq) was cooled to 0 ° C, triethylamine (0.30 mL, 4.0 eq) was added thereto in DMF solvent (5 mL) and the mixture was made to react for one day. The solvent was distilled under reduced pressure. The residue was extracted with ethyl acetate (30 mL x 2), washed with water, aqueous sodium hydrogen carbonate solution and sodium chloride solution. aqueous, dried (Na2SO < anhydrous) and concentrated under reduced pressure. The residue was separated by column chromatography (40-60% ethyl acetate-hexane) to give 233 mg (92%) of the 3- [2- (2-benzyl-5-methyl-) methyl butyl ester. 3-oxo-J ?, 3-dihydro-pyridazin-4-yl) butyrylamino] -5-fluoro-4-hydroxy-pentanoic acid. To this compound and the Dess-Martinj reagent (312 mg, 3.0 eq) was added anhydrous dichloromethane (4 mL), which was then stirred for 1 h at room temperature. The reaction was stopped by isopropyl alcohol (1 mL) !. The solid was removed by celite filtration under reduced pressure and extracted with ethyl acetate (20 mL x 2 ^.) The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried (a2 S04 anhydrous) and concentrated under reduced pressure The residue was separated by column chromatography (30-M0% ethyl acetate-hexane) to give 201 mg (79%) of the title compound J 1 H-NMR (500MHz, CDC13) d 8.13 (br s, 1H), 7.62 (s, 1H), 7 | .38-7.25 (m, 5H), 5.38-5.20 (m, 2 H), 5.20-4.80 (m, 2H) ), 4. 80-4.68 (m, 1H), 3.76 (m, 1H), 2.88-2.57 (m, 2H), 2.26 (s, 3H), 2.26-1.98 (m, 2H), 1.41 (m, 9H), 0.87 ( m, 3H)! Example 2) 3- [2- (2-Benzyl-5-methyl-3-oxo-2,3-dihydro-pyridaz n-4-yl) -butyrylamino] -5-fluoro-4-oxo-pentanoic acid ! The compound of Preparation 2-4) (198 mg, 0.418 mraol) was dissolved in dichloromethane (4 mL) and trifluoric acid was added | > Roacetic (2 mL) at 0 ° C. The mixture was stirred for 1 h, during which time it was slowly heated to room temperature. The mixture was concentrated under reduced pressure and separated by column chromatography (10% methanol-dichloromethane) to give 175 mg (stoichiometric yield, with poivo) of the title compound. 1H-NMR (500MHz, DMS0-d6) d 12.31 (br s, 1H), 7.95-7.86 (dcj, 1H), 7.79 (s, 1H), 7.28-7.22 (m, 5H), 5.34-4.86 (m, 4H), 4.49-4.39 (m, 1H), 3.60 (m, 1H), 2.70-2.35 (m, 2H), 2.14 (s, 3H), 2.j05-l.68 (m, 2H), 0.70 ( m, 3H) Preparation 3-1) 2-Benzyl-4, 5-dichloro-2H-pyridazin-3-one IA a mixture of 4,5-dichloro-2H-pyridazin-3-one (3.3 g, 20. q mmol) and Cs2C03 (9.77 mg, 1.5 eq) were added DMF (15 mL)! and benzyl bromide (3.10 mL, 1.3 eq), which was then stirred for 3 h at 60 ° C under nitrogen atmosphere. The mixture was concentrated under reduced pressure and the residue was extracted twice with ethyl acetate (200 mL). The extract was washed with aqueous sodium hydrogen carbonate solution, I saturated (NaHCO3, 100 mL x 2) and sodium chloride solution aqueous, dried (Na2SC> anhydrous) and concentrated under reduced pressure. The residue was separated by column chromatography (10% ethyl acetate-hexane) to give 4.48 g%) of the title compound. ^ -NR (500MHz, CDC13) d 7.77 (s, 1H), 7.43 (d, 2H), 7.35-7.30 (m, 3H), 5.32 (s, 2H) Preparation 3-2) Ethyl ester of acid (2- benzyl-5-chloro-3-oxo-2, 3-dihydrb-pyridazin-4-yl) -acetic Diethylmalonate (1.73 g, 1.64 mL, 2.5 eq) was dissolved in isopropyl ether (2 mL), sodium ethoxide was added (0.73 g, 2.5 eq) thereto at room temperature and the mixture was stirred for 30 min. To the reaction mixture was added the compound of Preparation 3-1) (1.10 g, 4.31 mmol), which was then heated to reflux for one day. The mixture was extracted with ethyl acetate (50 mL x 2), washed with aqueous sodium chloride solution (100 mL), dried (anhydrous Na 2 SO 4) and concentrated under reduced pressure. The residue was separated by column chromatography (10-20% ethyl acetate-hexane) to give 1.34 g (82%) of a 1: 1 mixture of 2- (2-benzyl-5-chloro) diethyl ester -3-oxo-2, 3-dihydro-pyridazin-4-yl) -malonic acid and diethyl ester of 2- (l-benzyl-5-chloro-6-oxo-l, 6-dihydro-pyridazin-4-yl) -malonic. This mixture was dissolved in 12 mL of a solvent mixture (H20: DMSO = 1: 5), NaCl was added. g, 5 eq) thereto and the mixture was heated at 120 ° C for one day. The mixture was concentrated under reduced pressure and the residue. it was extracted twice with ethyl acetate (200 mL).

The extract was washed with water, saturated sodium hydrogen carbonate solution (NaHCO 3, 100 mL x 2) and aqueous sodium chloride solution, dried (anhydrous Na 2 SO 4) and concentrated under reduced pressure. The residue was separated by column chromatography (10-20% ethyl acetate-hexane) for 530 mg (49%) of the title compound. I 1 H-NMR (500 MHz, CDC 13) d 7.76 (s, 1 H), 7.39 (d, 2 H), 7. 33-7.26 (m, 3H), 5.29 (s, 2H), 4.17 (qt, 2H), 3.75 (s, 2H), 1.24 (t, 3H) Preparation 3-3) Ethyl ester of (2-benzyl) acid 3-oxo-2,3-dihydro-pyridazin-4-yl) -acetic acid The compound of Preparation 3-2) (1.15 g, 3.75 I mmol) ie dissolved in 30 mL of EtOH, 10% Pd / C was added I (200 mfcf, Aldrich) and the mixture was stirred for 3 h under nitrogen atmosphere. The reaction mixture was passed through celite, washed twice with ethanol and the ethanol extract was concentrated under reduced pressure to give 1.00 g. (98%) of the title compound. i! 'H-NMR (500MHz, CDCl 3) d 7.7 (d, 1H), 7.42 (d, 2H), 7.33-7., 26 (m, 3H), 7.17 (d, 1H),. 5.33 (s, 2H), 4.18 (qt, 2H), 3.59 (s, 2H), 1.25 (t, 3H) Preparation 3-4) i 2- (2-Benzyl-3-oxo-2,3-dihydrp-pyridazin-4-yl) -butyric acid ethyl ester 'The compound of Preparation 3-3) (272 mg, 1.00 mmol) was dissolved in anhydrous THF (5 mL) under a nitrogen atmosphere and maintained at a temperature of -78 ° C. LiHMDS 1. OM / THF (1.50 mL, 1.5 eq) was added thereto and mixture j was stirred for 10 min. Ethyl iodide (0.14 mL, 1.8 eq) was added and the mixture was slowly warmed to room temperature, with stirring overnight. The ! The reaction was stopped by saturated ammonium acetate solution. The reaction mixture was extracted with ethyl acetate Ethyl (50 mL x 2), washed with aqueous sodium chloride solution (100 mL), dried (anhydrous a2SO4) and concentrated under reduced pressure. The residue was separated by column chromatography (10-20% ethyl acetate / hexane) to give 220 mg (73%, oil) of the title compound. i 1H-NMR (500MHz, CDC13) d 7.74 (d, 1H), 7.42 (d, 2H), 7.33-7..26 (m, 3H), 7.17 (d, 1H), 5.32 (ABq, 2H), 4.18-4.10 (m, 2H), 3. | 87 (t, 2H), 2.01-1.77 (m, 2H), 1.21 (t, 3H), 0.95 (t, 3H) Preparation 3-5) Tert-butyl ester 3- [2- (2-Benzyl-3-oxo-2, 3-dihydro-pyridazin-4-yl) -butyrylamino] -5-fluoro-4-yl-pentanoic acid The compound of Preparation 3- 4) hydrolyzed from I I agreed with the same procedure as Preparation 2-3) to dpr the carboxylic acid derivative. A mixture of this I derived from carboxylic acid (205 mg, 0.683 mmol), 3-amino-5-fluoro-4-hydroxy-pentanoic acid ter-bujyl ester (see Tetrahedron Letters, 1994, 35 (52), 9693-9696 , 170 mg, 1.2 eqj and HATU (337 mg, 1.3 eq) was cooled to 0 ° C, triethylamine (0.38 mL, 4.0 eq) was added thereto in DMF solvent (5 mL) and the mixture was reacted one day, the solvent was distilled under reduced pressure, the residue was extracted with ethyl acetate (30 mL x 2), washed with water, aqueous sodium carbonate hydrochloric solution and aqueous sodium chloride solution, dried ( Na2SO4 anhydrous) and concentrated under reduced pressure to give 3- [2- (2-benzyl-3-oxo-2,3-dihydro-pyridazin-yl) butyrylamino] -5-fluoro- tert -butyl ester. This compound and the Dess-Martin reagent (580 mg, 2.0 eq) were added with anhydrous dichloromethane (4 mL), which was then stirred for 1 h at room temperature. opium (1 mL) The solid was removed by celite filtration under reduced pressure and extracted with ethyl acetate (20 mL x 2). The extract was washed with water, aqueous sodium hydrogen carbonate solution, saturated < b and aqueous sodium chloride solution, dried (anhydrous Na 2 SO 4) and concentrated under reduced pressure. The residue was separated by column chromatography (20-30% ethyl acetate-hexane) to give 242 mg (77%) of the title compound. 1H-NMR (500MHz, CDC13) d 7.79 (m, 1H), 7.56 (m, 1H), 7. 42-7i27 (m, 5H), 7.14 (m, 1H), 5.40-5.27 (m, 2H), 5.22-4.67 (m, i 3H), 3.76 (m, 1H), 2.93-2.56 (m, 2H) , 2.16 (m, 1H), 1.69 (m, 1H), 1.42 & 1.38 (two s, 9H), 0.95 (m, 3H) Example 3) 3- [2- (2-Benzyl-3-oxo-2,3-dihydro-pyridazin-4-yl) -buyrylamino] acid - 5-fluoro-oxo-pentanoic The compound of Preparation 3-5) (242 mg, 0.527 mmol) was reacted according to the same procedure as Example 2) to give 195 mg (92%) of the title compound. XH-NMR (500MHz, DMSO-d6) d 12.40 (br s, 1H), 8.70 (m, 1H), 7.87 (m, 1H), 7.27-7.24 (m, 6H), 5.25-5.16 (m, 2H ), 5.21 (m, 2H), 4.58-4.47 (m, 1H), 3.6 (m, 1H), 2.69-2.47 (m, 2H), 1.72-1.62 (m, 2H), 0.82 (m, 3H) Preparation 4-1): Ethyl 2- (2-benzyl-5-chloro-3-oxo-2,3-dih-idro-pyridazin-4-yl) -butyric acid ethyl ester The compound of Preparation 3-2) ( 170 mg, 0.554 mmol) was reacted according to the same procedure as Preparation 3-4) to give 137 mg (74%) of the title compound. 1 H-NMR (500MHz, CDCl 3) d 7.74 (s, 1H), 7.38-7.26 (m, mmol) was dissolved in a solvent mixture (6 mL, tetrahydrofuran: MeOH: H20 = 3: 2: 1), LiOH.H20 (50 mg, 3.0 eq) was added thereto and the mixture was stirred for one day. . The reaction mixture was neutralized by 1N aqueous hydrochloric acid solution and distilled under reduced pressure to remove tetrahydrofuran almost completely. The residue was dissolved in excess ethyl acetate (50 mL), washed with additional . Preparation 4-3) i 3- [2- (2-Benzyl-5-chloro-3-OXO-2, 3-dihydro-pyridazin-4-yl) -butyrylamino] -5-fluoro tert-butyl ester -4-oxo-peiitanoic acid and 3- [2- (2-benzyl-5-methoxy-3-OXO-2,3-dihydro-pyridazin-4-yl) -butyrylamino] -5-fluoro- tert -butyl ester 4-oxo-pentanoic The two compounds obtained in Preparation 4-2) were reacted according to the same procedure as Preparation 2-4), and separated by column chromatography (30- ethyl acetate-hexane). 50%) to dir the chlorine derivative (45 mg, 23%) and the methoxy derivative I (62 mg, 32%). Chlorine derivative XH-NM (500MHz, CDC13) d 7.78 (s, 1H), 7.70 (m, 1H), 7.42-7.27 (m, 5H), 5.35-4.86 (m, 4H), 4.78-4.67 (m, 1H), .01 (m, 1H), 2.194-2.62 (m, 2H), 2.28-2.06 (m, 2H), 1.69 (m, 1H), 1.42 & 1. 41 (two s, 9H), 0.89 (m, 3H) Derivative of methoxy XH-NMR (500MHz, CDCI3) d 8.14-8.03 (br m, 1H), 7.84 (m, 1H), 7.40-7.26 (m, 5H) ), 5.40-4.70 (m, 5H), 3.94 (two s, 3H), 3.94 (m, 1H), 2.88-2.58 (m, 2H), 2.26-1.90 (m, 2H), 1.42 & 1.40 (two s, 9H), 0.86 (m, 3H) Example 4) 3- [2- (2-Benzyl-5-chloro-3-oxo-2,3-dihydro-pyridazin-4-yl) -butyrylamino] -5-fluoro-4-oxo-pentanoic acid I The chlorine compound of Preparation 4-3) (45 mg, 0.091 mmol) was reacted according to the same as Example 2) to give 23 mg (58%) of the composed of the title.; H-NMR (500MHz, DMS0-d6) d 8.17 (s, 1H), 7.97 (m, 1H), 7.40-7l23 (m, 5H), 5.36-5.29 (m, 1H), 5.29-4.70 (m, 2H) ), 5.09- 5.05 (m, 1H), 4.52-4.43 (m, 1H), 3.74 (m, 1H), 2.67-2.46 (m, 2H), 2. 10-lj74 (m, 2H), 0.73 (m, 3H) Example 5) 3- [2- (2-Benzyl-5-methoxy-3-oxo-2,3-dihydro-pyridazin-4-yl) acid - butyrylamino] -5-fluoro-4-oxo-pentanoic ! The methoxy compound of Preparation 4-3) (62 mg, 0.127 mmol) was reacted according to the same procedure as Example 2) to give 28 mg (51%) of the title compound. "" "H-NMR (500MHz, DMS0-d6) d 8.17 (s, 1H), 7.89-7.81 (m, 1H), 7.26-7.21 (m, 5H), 5.34-5.09 (Ab q, 2H), S .29-4.70 (m, 2H), 4. 52-41.40 (m, 1H), 3.90 (d, 3H), 3.62 (m, 1H), 2.65-2.46 (m, 2H), 1.97-1.64 (m, 2H), 0.68 (m, 3H) Preparation 6- 1) '4,5-Dichloro-2-methoxymethyl-2H-pyridazin-3-one j 4,5-Dichloro-2H-pyridazin-3-one (30 g, 182 mmol), N, N-diisopropylethylamine (47.5 mL , 258 mmol) and 4-dimetaminopyridine (2.20 g, 18.2 mmol) were dissolved in 200 mL of methylene chloride, to which chloromethyl methyl ether (16.6 mL, 21.8 mmol) was slowly added dropwise, while maintaining 0 ° C. The mixture was stirred for 3 h at room temperature. The reaction solution was washed with saturated aqueous sodium hydrogen carbonate solution, distilled under reduced pressure and separated, purified I by column chromatography (10% methylene chloride / ethyl acetate) to give the title compound (26.6 g, Yield: 70%) as a yellow solid. 1H-NMR (CDC13, 400 MHz) d 7.81 (s, 1H), 5.45 (s, 2H), 3.48 (s, i 3H) I Preparation 6-2) Diethyl ester of 2- (5-chloro-2- methoxymethyl-3-OXO-21, 3-dihydro-pyridazin-4-yl) -malonic acid and diethyl ester of 2- (5-chloro-l-methoxymethyl-6-oxo-l, 6-dihydro-pyridazin-4) -yl) -malonic The compound of Preparation 6-1) (26.6 g, 127 mmol) and sodium ethoxide (13 g, 191 mmol) were suspended in diisopropyl ether (100 mL) and stirred for 30 min. Diethyl malonate (29.0 mL, 191 mmol) was added thereto and the mixture was heated to reflux for one day. After completion of the reaction, the mixture was distilled under reduced pressure to remove the diisopropyl ether. The residue was dissolved again in methylene chloride, washed with 1N hydrochloric acid and aqueous sodium hydrogen carbonate solution], saturated and distilled under reduced pressure. The residue was separated by column chromatography (14.3% ethyl acetate / hexane) to give the title mixture in a ratio of 1: 1 (32 g, Yield: 76%) as a pale yellow liquid. Preparation 6-3) Ethyl ester of (5-chloro-2-methoxymethyl-3-oxo-2,3-dihydro-pyridazin-4-yl) -acetic acid The compound of Preparation 6-2) (32.0 g, 96.2 mmol ) and sodium chloride (228 g, 481 mmol) were dissolved in water / dimethyl sulfoxide (120 mL, 1/5) and stirred for 16 h at 170 ° C. The dimethyl sulfoxide was removed by distillation in vacuo. The residue was dissolved in methylene chloride, washed with water, distilled under reduced pressure, separated by column chromatography (33% ethyl acetate / hexane) to give the title compound (12 g, Yield: 48% ) as a colorless liquid.; 1H-NMR (CDC13, 500 MHz) d 7.78 (s, 1H), 5.42 (s, 2H), 4. 18 (t, 2H), 3.77 (s, 2H), 3.44 (s, 3H), 1.26 (q, 3H) Preparation 6-4) Ethyl ester of acid (2-methoxymethyl-3-oxo-2,3-dihydrp) -pyridazin-4-yl) -acetic The compound of Preparation 6-3) (405 mg, 1.55 mmol) was dissolved in 10 mL of EtOH, Pd was added at 10 / C (100 ntg, Aldrich) and the mixture was added. stirred for 1 h under a hydrogen atmosphere. The reaction mixture was passed through celite and washed twice with ethanol. The ethanol extract was concentrated under reduced pressure and separated by column chromatography (40 ^ 50% ethyl acetate / hexane) to give the title compound (240 mg, Yield: 68%) as a colorless liquid. 1H-NMR (500MHz, CDC13) d 7.76 (d, 1H), 7.21 (d, 1H), 5.45 (s, 2H), 4.18 (qt, 2H), 3.45 (s, 3H), 1.27 (t, 3H) ) II, j Preparation 6-5)! Ethyl 2- (2-methoxymethyl-3-oxo-2,3-dihydro-pyridazin-4-yl) -butyric acid ethyl ester The compound of Preparation 6-4) (240 mg, 1.06 mmol) was reacted according to with the same procedure as Preparation 2-2) to give 179 mg (67%) of the title compound. 1H-NMR (500MHz, CDC13) d 7.77 (d, 1H), 7.21 (d, 1H), 5.46 (m, '2H), 4.22-4.10 (m, 2H), 3.88 (m, 1H), 3.45 (s) , 3H), 2.00-1.78 (two m, 2H), 1.24 (t, 3H), 0.96 (t, 3H) Preparation 6-6) I Ethyl 2- (3-oxo-2,3-dihydro-pyridazin-4-yl) -butyric acid ethyl ester The compound of Preparation 6-5) (172 mg, 0.676 I mmol) was dissolved in 8 mL of CH2CI2, BBr3 (70 μ ?, or 1.1 eq / solution 1. OM in CH2Cl2) was added at -78 ° C and the mixture was stirred for 2 h while being heated slowly to temperature ambient. The reaction was stopped by saturated ammonium acetate. The reaction mixture was extracted with ethyl acetate and washed with aqueous sodium chloride solution). The extract was concentrated under reduced pressure and separated by Prep-TLC (70% ethyl acetate / hexane) to give the title compound (132 mg, Yield: 91%) as a colorless liquid. 1 H-NMR (500 MHz, CDCl 3) d 7.76 (d, 1 H), 7.26 (d, 1 H), I 4.18-4 J 10 (m, 2H), 3.88 (m, 1H), 2.00-1.75 (two m, 2H), 1.23 (t, 3H), 0 94 (t, 3H) Preparation 6-7) l- Bromomethyl-2-tert-butyl-benzene IA-l-tert-butyl-2-methyl-benzene (940 mg, 6.34 mmol), NBS (1.24 g, 1.1 eq) and AIBN (20 mg, catalytic amount) was added CC14 ( 12 mL), which was then heated to reflux for 1 h. The suspended particles were removed by filtration and washed with CC14. The organic layers were combined and concentrated under pressure reduced to give 1.5 g of a yellow liquid in a stoichiometric yield. XH-NMR (500MHz, CDC13) d 7.46 (m, 1H), 7.38 (m, 1H), 7.22-7.21 (m, 2H), 4.83 (s, 2H), 1.46 (s, 9H) Preparation 6-8) Ethyl 2- [2- (2-tert-butyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyric acid ethyl ester The compound of Preparation 6-6) (58 mg, 0.276 m or l) the compound of Preparation 6-7) (81 mg, 1.3 eq) I were reacted according to the same procedure as Preparation I-1) to give 53 mg (54%) of the title compound. : 1H-NMR (500MHz, CDC13) d 7.78 (d, 1H), 7.42 (d, 1H), 7.25 (m, 1H), 7.18 (d, 1H), 7.09 (t, 1H), 6.82 (d, 1H) ), 5.66 (ABq, 2H), 4.21-4.10 (m, 2H), 3.94 (t, 1H), 2.03-1.80 (two m, 2H), 1.49 (s, 9H), 1.23 (t, 3H), 0.97 (t, 3H) Preparation 6-9) 3-2- [2- (2-tert-Butyl-benzyl) -3-OXO-2,3-dihydro-pyridazin-4-yl] -butyl tert-butyl ester Butyrylamino-5-fluoro-4-oxo-pentanoic The compound of Preparation 6-8) (53mg, 0.149mmol) was reacted according to the same procedure as Preparation 3-5) to give 46 mg (60%) of the title comjpuesto. 1 1 H-NMR (500MHz, CDCI 3) d 7.84 (two d, 1H), 7.52 (m, ??), 7.43 (two s, 1H), 7.23-7.09 (m, 2H), 7.08 (two d, .1H), 5.71 & 5.66 (two s, 2H), 5.21-. 0 (m, 3H), 3.81 (m, 1H), 2.91-2.58 (m, 2H), 2.17 (m, 1H), 1.72 (m, 1H), 1.50 (s, 9H), 1.40 & 1.36 (two s, 9H), 0.97 (m, 3H) Example 6) 3-2- [2- (2-tert-Butyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl acid ] -butyrylamino-5-fluoro-4 - ??? - pentanoic compound of Preparation 6-9) (46 mg, 0.089 mmol) was reacted according to the same procedure as Example 2) to give the title compound (29 mg, 71%). 1H-NMR (500MHz, DMS0-d6) d 8.65-8.61 (m, 1H), 7.93 (q, 1H), 7.39-7.34 (m, 2H), 7.14 (t, 1H), 7.04 (t, 1H), 6.67 (m, 1H), 5.50 (Ab, q, 2H), 5.02 (m, 2H), 4.58-4.48 (m, 1H), 3.69 (m, 1H), 2.63 (m, 2H), 1.75-1.64 (m, 2H), 1.40 (s, 9H), 0.83 (m, 3H) I Preparation 7-1) 1-Bromomene-3-tert-butyl-benzene A-methyl-3-tert-butyl Benzene (551 mg, 3.72 mmol), NBS (730 mg, 1.1 eq) and AIBN (14 mg, catalytic amount) were added with CC1 (8 mL), which was then heated to reflux for 2 h. The suspended particles were removed by filtration and washed with CC14. The organic layers were combined and concentrated under reduced pressure to give 860 mg of a yellow liquid (which was identified by NMR to contain about 15% of the dibromo derivative). I! 1H-NMR (500MHz, CDC13) d 7.39-7.19 (m, 4H), 4.51 (s, 2H), 1.35 (s, 9H) Preparation 7-2) Ethyl ester of 2- [2- (3-ter- butyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyric acid To a mixture of the compound of Preparation 6-6) (50 mg, 0.238 mmol) and Cs2CO3 (116 mg, 1.5 eq ) DMF (B mL) and l-bromomethyl-3-tert-butyl-benzene from Preparation 7-1) (70 mg, 1.3 eq) were added, which was then stirred for 1 h at 60 ° C under nitrogen atmosphere . The mixture was concentrated under reduced pressure and the residue was extracted twice with ethyl acetate (50 mL). The extract was washed with saturated aqueous sodium hydrogen carbonate solution (NaHC03, 30 mL x 2) and aqueous sodium chloride solution, dried (N & 2S04 anhydrous) and concentrated under reduced pressure. The residue was separated by Prep-TLC (30% ethyl acetate-hexane) to give 57 mg (67%) of the title compound. i 1 H-NMR (500MHz, CDC13) 5 '7.74 (d, 1H), 7.43 (s, 1H), 7.30-7.16 (m, 4H), 5.32 (ABq, 2H), .18- .10 (m, 2H ), 3.88 (t, 1H), 1.99-1.76 (two m, 2H), 1.29 (s, 9H), 1.20 (t, 3H), 0.95 (t, 3H) Preparation 7-3) 3-2- [2- (3-tert-Butyl-benzyl) -3-OXO-2, 3-dihydro-pyridazin-4-yl] -butyrylamino-5-tert-butyl ester Fluoro-4-oxo-pentanoic The compound of Preparation 7-2) (56 mg, 0.157 mmol) was reacted according to the same procedure as Preparation 3-5) to give the title compound (49 mg, 60%). H-NMR (500MHz, CDCI3) d 7.79 (two d, 1H), 7.58 (m, 1H), 7 j.42 (two s, 1H), 7.32-7.14 (m, 4H), 5.35-5.28 (m, 2H), 5.21-4.¡68 (m, 3H), 3.75 (m, 1H) , 2.91-2.58 (m, 2H), 2.1 (m, 1H), 1.69 (m, 1H), 1.43 & 1.41 (two s, 9H), 1.29 (s, 9H), 0.95 (m, 3H) Example 7) 3-2- [2- (3-tert-Butyl-benzyl) -3-OXO-2, 3- acid dihydro-pyridazin-4-yl] -butyrylamino-5-fluoro-4-pyr-5-pentanoic acid The compound of Preparation 7-3) (48 mg, 0.0931 mmol) j was reacted according to the same procedure as Example 2) to give the title compound (31 mg, 72%). ! 1H-NMR (500MHz, DMSO-d6) d 8.65 (m, 1H), 7.89 (q, 1H), 7. 31 (t, 1H), 7.27 (s, 1H), 7.26 (m, 1H), 7.19 (t, 1H), 7.00 (m, 1H), 5.21 (m, 2H), 5.20-4.67 (m, 2H), 4.57-4.48 (m, 1H), 3.68 (m, 1H), 2.62 (m, 2H), 1.73-1.63 (m, 2H), 1.20 (s, 9H), 0.83 (m, 3H) j Preparation 8-1) Ethyl 2- [2- (2-methyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyric acid ethyl ester The compound of Preparation 6-6) (98 mg, 0.47 mmol) and l-bromomethyl-2-methylbenzene (112 mg, 1.3 eq) were reacted according to the same procedure as Preparation 2-1) to give the title compound (118 mg1, 80%). XH-NMR (500MHz, CDC13) d 7.75 (d, 1H), 7.20-7.13 (m, 5H), 5. 0-5.31 (ABq, 2H), 4.20-.10 (m, 2H), 3.89 (m, 1H), 2.40 (s, 3H), 1.97 (m, 1H), 1.82 (m, 1H), 1.22 (t, 3H), 0.96 (t, 3H) j Preparation 8-2) i Tert-butyl acid ester 5-Fluoro-3-2- [2- (2-methyl-benzyl) -3-oxo-2,3-dihydro-pyridazin = 4-yl] -butyrylamino-4-oxo-pentanoic The compound of Preparation 8- 1) (118 mg, 0.38 mmol) was reacted according to the same procedure as Preparation 3-5) to give the title compound (145 mg, 82%).; 1H-NMR (500MHz, CDC13) d 7.80 (two d, 1H), 7.57 (m, 1H), 71.20-7.13 (m, 5H), 5.38-5.35 (two s, 2H), 5.21-4.68 (m, 3H), 3.77 (m, 1?), 2.91-2.57 (m, 2H), 2.42 & 2.41 (two s, 3H), 2.15 (m, 1H), 1.70 (m, 1H), 1.43 & 1.39 (two s, 9H), 0.95 (m, 3H) Example 8) 5-Fluoro-3-2- [2- (2-methyl-benzyl) -3-oxo-2,3-dihydr-pyridazin-4 acid -yl] -butyrylamino-4-oxo-pentanoic The compound of Preparation 8-2) (143 mg, 0.302 mmol) was reacted according to the same procedure as Example 2) to give the title compound (109 mg, 87%). 1 H-NMR (500MHz, DMSO-dg) d 12.40 (br 8.63 (m, 1H), 7.88 (m, 1H), 7.31 (ra, 1H), 7.14 (m, 1H) 9 (t, 1H), 5.28- 4.95 (m, 4H), 4.58-4.48 (m 1H), 2.69-2.47 (m, 2H), 2.29 (s, 3H), 1.73-1.64 (m 3H) Preparation 9-1) Ethyl ester of 2-acid [2- (3-methyl-benzyl) -3-oxo-2,3-dih! Idro-pyridazin-4-yl] -butyric The compound of Preparation 6-6) (103 mg, 0.49 L-bromomethyl-3 -methylbenzene (118 mg, 1.3 eq) is reacted according to the same procedure Preparation 2-1) to give the title compound i XH-NMR (500MHz, CDC13) d 7.74 (d, 1H), 7.22-7.08 (m, 4H), .08 (m, 1H), 5.33-5.24 (ABq, 2H), 4.20-4.01 (m, 2H) , 3.88 (mj 1H), 2.32 (s, 3H), 1.95 (m, 1H), 1.81 (m, 1H), 1.21 (t, 3H), 0i95 (t, 3H) Preparation 9-2) Ter-butyl ester of 5-fluoro-3-2- [2- (3-methyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyrylamino-4-oxo-pentanoic acid The compound of Preparation 9-1) (110 mg, 0.35 mmol) was reacted according to the same procedure as Preparation 3-5) to give the tirulo compound (141 mg, 89%). I 1 H-NMR (500 MHz, CDC 13) d 7.79 (two d, 1 H), 7.59 (m, 1H), 7'.22-7.08 (m, 5H), 5.36-4.69 (m, 5H), 3.75 (m, 1H), 2.92-2.59 (m; 2H), 2.32 (two s, 3H), 2.15 ( m, 1H), 1.70 (m, 1H), 1.44 & 1. 1 [2 s, 9H), 0.95 (m, 3H) Example 9) 5-Fluoro-3-2- [2- (3-methyl-benzyl) -3-OXO-2, 3-dihydroxy acid pyridazin-4-yl] -butyrylamino-4-oxo-pentanoic acid 1 The compound of Preparation 9-2) (137 mg, 0.289 mmol) 1 was reacted according to the same procedure as Example 2) to give the compound of Title . (104 mg, 86%). 1H-NiiR (500MHz, DMSO-d6) d 12.41 (br s, 1H), 8.72-8.64 (m, 1H), 7.87 (m, 1H), 7.29 (s, 1H), 7.16 (t, 1H), 7.05 (m, 3H), 5j.26-4.92 (m, 4H), 4.58-4.47 (m, 1H), 3.66 (m, 1H), 2.69-2.47 (m, 2H), 2.22 (s, 3H), 1.73-1.63 (m, 2H), 0.83 (m, 3H) Preparation 10-1) Ethyl 2- [2- (3-methoxy-benzyl) -3-oxo-2,3-dihydro-pyridazin-2-ethyl ester -yl] -butyric The compound of Preparation 6-6) (114 mg, 0.54 mmol) and 1-bromomethyl-3-methoxy-benzene (142 mg, 1.3 eq) were reacted according to the same procedure as Preparation 2-1) to give the title compound (145 mg, 81%). 1 H-NMR (400MHz, CDC13) d 7.79 (d, 1H), 7.25 (t, 1H), 7.22 (d, 1H), 7.03 (d, 1H), 7.00 (s, 1H), 6.87 (d, 1H) ), 5.40- I 5.30 (Aq, 2H), 4.21-4.13 (m, 2H), 3.93 (t, 1H), 3.82 (s, 3H), 1. 98 (m, | 1H), 1.85 (m, 1H), 1.26 (t, 3H), 1.00 (t, 3H) Preparation 10-2) 5-Fluoro-3-2- [2- tert -butyl ester] (3-methoxy-benzyl) -3-oxo-2, 3-dihydro-pyridazin-4-yl] -butyryl-amino-4-oxo-pentanoic The compound of Preparation 10-1) (145 mg, 0.44 mol ) was reacted according to the same procedure as the > Preparation 3-5) to give the title compound (70 mg, 33%). 1 H-NMR (500 MHz, CDCl 3) d 7.79 (two d, 1 H), 7.58 (m, 1 H), 7.23 (t, 1 H), 7.15 (two d, 1 H), 7.00-6.90 (m, 2 H), 6.81 ( m, 1H), 5.32 (m, 2H), 5.30-4.68 (m, 3H), 3.77 (s, 3H), 3.7 (m, 1H), 2.92-2Í58 (m, 2H), 2.15 (m, 1H) , 1.68 (m, 1H), 1.43 & 1.40 (two s, 9H), 0.95 (m, 3H) Example 10) 5-Fluoro-3-2- [2- (3-methoxy-benzyl) -3-oxo-2,3-dihydro-pyridazin-4 acid -yl] -butyrylamino-4-oxo-pentanoic The compound of Preparation 10-2) (70 mg, 0.14 mmol) was reacted according to the same procedure as Example 2) to give the title compound (56 mg, 90%). j 1H-NMR (500MHz, DMSO-d6) d 8.64 (br s, 1H), 7.88 (m, 1H), 730 (m, 1H), 7.19 (m, 1H), 6.80-6.77 (m, 3H), 5.41-4.80 (m, 2H), 5.28-5.1 (m, 2H), 4.57-4.49 (m, 1H), 3.67 (m, 3H), 3.65 (m, 1H), 2 71-2.32 (m, 2H), 1.74-1.63 (m, 2H), 0.82 (m, 3H) í! Preparation 11-1) Ethyl 2- (2-naphthalen-l-ylmethyl-3-oxo-2,3-clihydro-pyridazin-4-yl) -butyric acid ethyl ester I I The compound of Preparation 6-6) (98 mg, 0.47 mmol) and 1-chloromethyl-naphthalene (107 mg, 1.3 eq) were reacted according to the same procedure as the Preparation 2-1) to give the title compound (81 mg, 50%). 1H-NMR (500MHz, CDC13) d 8.29 (d, 1H), 7.87-7.79 (m, 2H), 7.73 (d, 1H), 7.56-7.42 (m, 4H), 7.16 (d, 1H), 5.86- 5.73 (A0q, 2H), 4.20-4.10 (m, 2H), 3.90 (m, 1H), 1.97 (m, 1H), 1.82 (m, 1H), 1.20 (t, 3H), 0.95 (t, 3H) Preparation 11-2) 5-Fluoro-3- [2- (2-naphthalen-1-ylmethyl-3-oxo-2,3-dihydro-pyridazin-4-yl) -butyryl-amino] tert-butyl ester -4-oxo-pentanoic The compound of Preparation 11-1) (81 mg, 0.23 mmol) was reacted according to the same procedure as Preparation 3-5) to give the title compound (82 mg, 70 mg). %). XH-NMR (400MHz, CDC13) d 8.32 (two d, 1H), 7.91- 7.81 (m, 3H), 7.65-7.46 (m, 5H), 7.19 (m, 1H), 5.89-5.80 (m, 2H) , 5.28-4.75 (m, 3H), 3.83 (m, 1H), 2.96-2.65 (m, 2H), 2.18 (m, 1H), 1.75 (m, 1H), 1.47 & 1.42 (two s, 9H), 0.99 (m, 3H) Example 11) 5-Fluoro-3- [2- (2-naphthalen-1-ylmethyl-3-yl-2, 3-dihydro-pyridazin-) acid 4-yl) -butyrylamino] -4-oxo-pentanoic acid The compound of Preparation 11-2) (82 mg, 0.16 mmol) was reacted according to the same procedure as Example 2) to give the title compound (57 mg, 78%). 1H-NMR (500MHz, DMSO-d6) d 8.66 (br s, 1H), 8.20 (d, 1H), 7.93-7.84 (m, 3H), 7.52 (m, 2H), 7.42 (m, 1H) , 7.31 (m, 1H), 7.26 (m; 1H), 5.70 (m, 2H), 5.43-4.80 (m, 2H), 4.55-4.48 (m, 1H), 3.72 (m, 1H), 2.70-2.33 (m, 2H), 1.75-1.65 (m, 2H), 0.84 (m, 3H) Preparation 12-1) Ethyl 2- (2-naphthalen-2-ylmethyl-3-oxo-2,3-dihydro) ethyl ester -pyridazin-4-yl) -butyric The compound of Preparation 6-6) (97 mg, 0.46 mmol) and 2-bromomet-il-naphthalene (132 mg, 1.3 eq) were reacted according to the same procedure as the Preparation 2-1) to give the title compound (91 mg, 57%). i 1H-NMR (500MHz, CDC13) d 7.88 (s, 1H), 7.83-7.78 (m, 3H), 7 i 76 (d, 1H), 7.56 (d, 1H), 7.47-7.44 (m, 2H) , 7.18 (d, 1H), 5.53-5.43 (ABq, 2H), 4.20-4.10 (m, 2H), 3.88 (m, 1H), 1.95 (m, 1H), lj82 (m, 1H), 1.19 (t, 3H), 0.95 (t, 3H)! Preparation 12-2) 5-Fluoro-3- [2- (2-naphthalen-2-ylmethyl-3-oxo-2,3-dihydro-pyridazin-4-yl) -butyryl-amino-tert-butyl ester] j4-oxo-pentanoic The compound of Preparation 12-1) (91 mg, 0.26 mmol) was reacted according to the same procedure as Preparation 3-5) to give the title compound i (83 mg, 63%). 1H-NR (400MHz, CDC13) d 7.91 (d, 1H), 7.87-7.83 (m, 4H), 7.66-7.56 (m, 2H), 7.53-7.48 (m, 2H), 7.20 (t, 1H), 5.60-5.52 (m, 2H), 5.28-4.75 (m, 3H), 3.82 (m, 1H), 2.94-2.65 (m, 2H), 2.19 (m, 1H), 1.74 (m, 1H), 1.47 &; 1.44 (two s, 9H), 1.00 (m, 3H) Example 12) 5-Fluoro-3- [2- (2-naphthalen-2-ylmethyl-3-oxo-2,3-di-idro-pyridazin-4-yl) -butyrylamino] -4-oxo-pentanoic acid The compound of Preparation 12-2) (83 mg, 0.16 i mraol) was reacted according to the same procedure as Example 2) to give the title compound (68 mg, 92%). XH-NMR (500MHz, DMSO-d6) d 8.64 (br s, 1H), 7.90 (m, 1H), 7.j85-7.83 (m, 3H), 7.76 (s, 1H), 7.46 (m, 2H), 7.42 (m, 1H), 7. 31 (m, | lH), 5.44-5.34 (m, 2H), 5.31-4.73 (m, 2H), 4.57-4.49 (m, 1H), 3.69 (m, 1H), 2.63-2.32 (m, 2H) , 1.75-1.63 (m, 2H), 0.82 (m, 3H) Preparation 13-1) '(2-Methyl-oxazol-4-yl) -methanol To LiAlH4 (304mg, 1.5 eq) was added anhydrous THF (20 mL). Methyl ester of 2-methyl-oxazole-4-carboxylic acid (see J, of Org. Chem., 2003, 68, pages 4215-4234) dissolved in THF (20 mL) was added thereto at -78 ° C and stirred for 1 h at the same temperature. The reaction was stopped by water. The reaction mixture was passed through celite.and extracted with ethyl acetate (50 mL x 3). The organic layer i was washed with aqueous sodium chloride solution, distilled under reduced pressure and separated by column chromatography (ethyl acetate) to give the title compound (308 mg, Yield: 51%) as a solid pale yellow. 1H-NMR (400MHz, CDC13) d 7.48 (s, 1H), 4.56 (d, 2H), 2.45 (s, | 3H), 2.18 (t, 1H) Preparation 13-2) j 4-Bromomethyl-2-methyl -oxazole The compound of Preparation 13-1) (307 mg, 2.71 mmol) was dissolved in CH2C12 (20 mL), CBr4 (1.17 g, 1.3 eq) and 1 PPh3 (1.07 g, 1.5 eq) was added thereto and the mixture was 3 h. The reaction mixture was dried under pressure was separated by column chromatography (25% ethyl acetate / hexane) to give the title compound (139 mg, Yield: 29%) as a colorless liquid. i 1 H-NMR (400MHz, CDCl 3) d 7.58 (s, 1H), 4.39 (s, 2H), 2.50 (s, 3H) 1 Preparation 13-3) Ethyl 2- [2- (2-methyl-oxazol-4-ylmethyl) -3 - ?? - 2, 3-dihydro-pyridazin-4-yl] -butyric acid ethyl ester j The compound of Preparation 6-6 ) (160 mg, 0.761 mmol) ly and 4-bromomethyl-2-methyl-oxazole (139 mg, 1.3 eq) were reacted according to the same procedure as Preparation 2-1) to give the title compound (159 mg, 69%). XH-NMR (500MHz, CDC13) d 7.77 (d, 1H), 7.56 (s, 1H), 7. 18 (d, 1H), 5.19 (ABq, 2H), 4.20- .10 (m, 2H), 3.86 (t, 1H), 1.98-1! 74 (two m, 2H), 1.22 (t, 3H), 0.94 (t, 3H) I Preparation 13-4) 5-Fluoro-3-2- [2- (2-methyl-oxazol-4-ylmethyl) -3-oxo-2,3-dihydro-tert-butyl ester -pyridazin-4-yl] -butyrylamino-4-oxo-pentanoic acid The compound of Preparation 13-3) (155 mg, 0.508 mmol) was reacted according to the same procedure as Preparation 3-5) to give the title compound (150 mg, 64%). 1H-NMR (500MHz, CDC13) d 7.80 (two d, 1H), 7.60-7.55 (m, 2H), 7.15 (m, 1H), 5.30-4.69 (m, 5H), 3.75 (m, 1H), 2.93 -2. | 62 (m, 2H), 2.39 & 2.37 (two s, 3H), 2.12 (m, 1H), 1.66 (m, | lH), 1.41 & 1.38 (two s, 9H), 0.92 (m, 3H) Example 13) 5-Fluoro-3-2- [2- (2-methyl-oxazol-4-ylmethyl) -3-oxo-2,3-dihydro acid -pyridazin-4-yl] -butyrylamino-4-oxo-pentanoic acid The compound of Preparation 13-4) (150 mg, 0.323 mmol) was reacted according to the same procedure as Example 2) to give the title compound (113 mg, 86%). 1 H-NMR (500MHz, DMSO-d 5) d 12.41 (br s, 1H), 8.70-8.63 (dd, 1H), 7.85 (m, 1H), 7.78 (m, 1H), 7.30 (m, 1H), 5.24 -4.97 (m, 4H), 4.59-4.46 (m, 1H), 3.63 (m, 1H), 2.82-2.47 (m, 2H), 2.30 (sj 3H), 1.73-1.63 (m, 2H), 0.83 ( m, 3H) Preparation 14-1) Ethyl 2- [2- (2-methyl-thiazol-4-ylmethyl) -3-OXO-2, 3-dihydro-pyridazin-4-yl] -butyric acid ethyl ester The compound of Preparation 6-6) (98 mg, 0.47 mmol) j and 4-bromomethyl-2-methyl-thiazole (112 mg, 1.3 eq, LancastJer) were reacted according to the same procedure as Preparation 2-1) for give the title compound (101 mg, 67%). 1H-NMR (500MHz, CDC13) d 7.79 (d, 1H), 7.20 (d, 1H), 7.05 (s "1H), 5.45-5.37 (ABq, 2H), .20- .10 (m, 2H), 3.88 (t, 1H), 2.68 (s, 3H), 1.96 & 1.81 (two m, 2H), 1.22 (t, 3H), 0. 95 (t, 3H) Preparation 14-2) 5-Fluoro-3-2- [2- (2- I-thiazol-4-ylmethyl) -3-oxo-2, 3-dihydro-pyridazin-4-yl] -buylamino-4-oxo-pentanoic acid The compound of Preparation 14-1) (101 mg, 0.31 g) mmol) 1 was reacted according to the same procedure as Preparation 3-5) to give the title compound (32 mg, 21%). 1H-NMR (500MHz, CDC13) d 7.83 (two d, 1H), 7.58 (m, 2H), 7j.20-7.03 (m, 2H), 5.51-4.69 (m, 5H), 3.75 (m, 1H) , 2.93-2.62 (m, 2H), 2.64 (m, 3H), 2.12 (m, 1H), 1.66 (m, 1H), 1.41 & 1.38 (mj 9H), 0.94 (m, 3H) Example 14) j 5-Fluoro-3-2- [2- (2-methyl-thiazol-4-ylmethyl) -3-oxo-2,3-dihydroxy acid pyridazin-4-yl] -butyrylamino-4-oxo-pentanoic acid aration 14-2) (32 mg, 0.066 mmol) was reacted according to the same procedure as Example 2) to give the title compound (16 mg, 58%). i 1 H-NMR (500MHz, CDCl 3) d 7.82 (m, 1H), 7.80-7.76 (dd, 1H), 7.25 (s, 1H), 7.12 (m, 1H), 6.07-6.91 (m, 1H), 5.15 -4.57 (m, 4H), 3J90 (m, 1H), 2.92-2.75 (m, 2H), 2.67 (s, 3H), 2.22-1.67 (m, 2H), 0.97 (m, 3H) Preparation 15-1) j 2- [2- (3,5-Dimethyl-isoxazol-4-ylme-yl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyric acid ethyl ester I The compound of Preparation 6 -6) (96 mg, 0.46 mmol) and 4-chloromethyl-3,5-dimethyl-isoxazole (86 mg, 1.3 eq, Aldrich) were reacted according to the same procedure as Preparation 2-1) to give the compound of the title (119 mg, 82%). I 1 H-NMR (500 MHz, CDC 13) d 7.71 (d, 1 H), 7.18 (d, 1 H), 5. 10-5.02 (ABq, 2H), 4.20-4.10 (m, 2H), 3.85 (t, 1H), 2.46 (s, I 3H), 2 | .32 (s, 3H), 1.98-1.74 (two m, 2H), 1.22 (t, 3H), 0.95 (t, 3H) j Preparation 15-2) 3-tert-butyl ester of acid -2- [2- (3, 5-dimethyl-isoxazol-4-ylmethyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyrylamino-5-fluoro-4-oxo-pentanoic acid j compound of Preparation 15-1) (119 mg, 0.37 mmol): was reacted according to the same procedure as Preparation 3-5) to give the title compound (47 mg, 40%). 1H-NMR (400MHz, CDC13) d 7.79 (two d, 1H), 7.48 (m, 1H), 7L21 (d, 2H), 5.30-4.79 (m, 5H), 3.77 (m, 1H), 2.97-2.69 (m, 2H), 2.54 (two s, 3H), 2.36 (s, 1H), 2.16 (m, 1H), 1.72 (m, 1H), 1.47 & 1.42 (two s, 9H), 0.99 (m, 3H) Example 15) j 3-2- [2- (3,5-Dimethyl-isoxazol-4-ylmethyl) -3- acid oxo-2, 3-dihydro-pyridazin-4-yl] -butyrylamino-5-fluoro-4-yl-pentanoic acid The compound of Preparation 15-2) (47 mg, 0.098 mmol) was reacted according to the same procedure as Example 2) to give the title compound: (27 mg, 66%). l Ht-NMR (500MHz, DMSO-dg) d 8.64 (br s, 1H), 7.86 (dd, 1H), 7i28 (m, 1H), 5.32-4.91 (m, 2H), 5.08-4.96 (m, 2H ), 4.56-4.47 (m, 1H), 3.66 (m, 1H), 2.63-2.32 (m, 2H), 2.37 (s, 3H), 2. 16 (s, (3H), 1.72-1.63 (m, 2H), 0.82 (m, 3H) ij Preparation 16-1) Ethyl 2- (2-cyclohexylmethyl-3-oxo- 2,3-dihydro-) ethyl ester pyridazin-4-yl) -butyric The compound of Preparation 6-6) (101 mg, 0.48 mmol) and bromomethyl-cyclohexane (111 mg, 1.3 eq, Aldrich) were reacted according to the same procedure as the Preparation 2-1) to give the title compound (82 mg, 56%).; XH-NMR (500MHz, CDC13) d 7.71 (d, 1H), 7.16 (d, 1H), 4.20-4. 10 (m, 2H), 4.14-3.94 (m, 2H), 3.86 (t, 1H), 1.98- i 1.74 (two m, 2H), 1.72-1.60 (broad m, 5H), 1.23 (t, 3H) ), 1.20-1.16 (broad m, 3H), 1.05-1.00 (m, 2H), 0.96 (t, 3H) I Preparation 16-2) 3- [2- (2-Cyclohexylmethyl-3-oxo-2,3-dihydro-pyridazin-4-yl) -butyryl-amino] -5-fluoro-4-tert-butyl ester oxo-pentanoic ^ The compound of Preparation 16-1) (80 mg, 0.26 mmol)! was reacted according to the same procedure as Preparation 3-5) to give the title compound (106 mg, 88%). "" "H-NMR (500MHz, CDC13) d 7.77 (m, 1H), 7.64 (m, 1H), 7.1 (mL 1H), 5.29-4.72 (m, 3H), .10-3.98 (m, 2H) , 3.76 (m, 1H), 2.94-2.62 (m, 2H), 2.15 (m, 1H), 1.94 (m, 1H), 1.72-1.60 (broad m, 5H), 1.43 & 1.41 (two s, 9H ), 1.23-1.00 (m, 5H), 0.96 (m, 3H) j Example 16) 3- [2- (2-Cyclohexylmethyl-3-oxo-2,3-dihydro-pyridazin-4-yl) -butyrylamino acid ] -5-fluoro-4-oxo-pentanoic The compound of Preparation 16-2) (106 mg, 0.23 mmol) I was reacted according to the same procedure as Example 2) to give the title compound! (71 mg, 76%). 1H-NMR (500MHz, DMS0-d6) d 8.65 (br s, 1H), 7.83 (m, 1H), 7.26 (m, 1H), 5.35-4.88 (m, 2H), 4.57-4.48 (m, 1H) , 3.97- i 3.82 (m 2 H), 3.63 (m, 1 H), 2.66-2.47 (m, 2 H), 1.79 (m, 1 H), 1.73 (m ,: 1 H), 1.61 (m, 3 H), 1.55 (m, 1H), 1.49 (m, 2H), 1.10 (m, 3H), 0.95 (ra, 2H), 0.82 (m, 3H) Preparation 17-1) j 1-Bromomethyl-isoquinoline i A 1-methylisoquinoline (0.99 g, 6.91 mmol), NBS (1.35 g, 1.1 eq) and AIBN (10 mg, catalytic amount) was added CC14 (IS mL), which was heated to reflux for 2 h. The suspended particles were removed by filtration and washed with CC14. The organic layers were combined, concentrated under reduced pressure and separated by column chromatography (1% ethyl acetate / hexane) to give the title compound (270 mg, Retrieval: 18%) as a violet solid. j 1 H-NMR (500MHz, CDCl 3) d 8.48 (d, 1H), 8.25 (d, 1H), 7.87 (d, 1H), 7.75-7.67 (two t, 2H), 7.65 (d, 1H) Preparation 17- 2) Ethyl 2- (2-isoquinolin-1-ylmethyl-3-yl-2,3-dihydro-pyridazin-4-yl) -butyric acid ethyl ester The compound of Preparation 6-6) (110 mg, 0.52 mmol) and 1-bromomethyl-isoquinoline (151 mg, 1.3 eq) obtained in Preparation 17-1) were reacted in accordance with I the same procedure as Preparation 2-1) to give the title compound (135 mg, 73%). 1H-NMR (500MHz, CDC13) d 8.42 (d, 1H), 8.26 (d, 1H), i 7.82 (dj 1H), 7.77 (d, 1H), 7.60 (t, 1H), 7.57 (d, 1H), 7.22 (d, 1H), 6j06-5.91 (ABq, 2H), 4.21-4.10 (m, 2H), 3.91 (t, 1H), 2.01-1.78 (dos m, 2H), 1.21 (t, 3H), 0.96 (t, 3H) Preparation 17-3) Tert-butyl ester of 5-fluoro-3-acid [2- (2-isoquiriolin-l-ylmethyl-3-oxo-2,3-dihydro-pyridazin-4-yl) -butyrylamino] -4-oxo-pentanoic acid The compound of Preparation 17-2) (130 mg, 0.37 mmol) was reacted according to the same procedure as Preparation 3-5) to give the title compound (150 mg, 79%). 1H-NMR (500MHz, CDC13) d 8.39 (d, 1H), 8.27 (d, 1H), 7.88-7.80 (m, 2H), 7.73-7.56 (m, 3H), 7.22 (m, 1H), 6.12- 5.95 (m, 2H), 5.23-4.68 (m, 3H), 3.80 (m, 1H), 2.92-2.58 (m, 2H), 2.19 (m, 1H), 1.75 (m, 1H), 1.34 (m, 9H), 0.96 (m, 3H) Example 17) 5-Fluoro-3- [2- (2-isoquinolin-l-ylmethyl-3-oxo-2,3-dihydro-pyridazin-4-yl) -butyrylamino acid] -4-oxo-pentanoic The compound of Preparation 17-3) (150 mg, 0.29 mmol) was reacted according to the same procedure as Example 2) to give the title compound. (123 mg, 92%). 1H-NMR (500MHz, DMSO-d6) d 12.42 (br s, 1H), 8.74-8.64 (dd, 1H), 8.28 (m, 2H), 7.98 (d, 1H), 7.87 (m, 1H), 7.79 (m, 1H), 7.72-7.65 (m, 2H), 7.3 (m, 1H), 5.92 (m, 2H), 5.22-5.00 (m, 2H), 41.60-4.48 (m, 1H), 3.67 (m, 1H) , 2.74-2.54 (m, 2H), 1.77-1.65 (mi 2H), 0.84 (m, 3H) Preparation 18-1) Ethyl 2- [2- (2-chloro-benzyl) -3-oxo- 2,3-dihydro-pyridazin-4-yl] -butyric i The compound of Preparation 6-6) (100 mg, 0.476 mriol) and l-bromomethyl-2-chlorobenzene (127 mg, 1.3 eq, Aldriclji) were made react according to the same procedure as Preparation 2-1) to give the title compound (92 mg, 58%). XH-NMR (500MHz, CDCl3) d 7.77 (d, 1H), 7.37 (d, 1H), 3H), 7.07 (d, 1H), 5.51-5. 3 (ABq, 2H), 4.21- 3.90 (t, 1H), 2.02-1.79 (two m, 2H), 1.22 (t, 3H), eparation 18-2) 3- tertiary butyl ester. { 2- [2- (2-Chloro-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyrylamino} -5-fluoro-4-oxo-pentanoic j The compound of Preparation 18-1) (92 mg, 0.275 mmol) I was reacted according to the same procedure as Preparation 3-5) to give the title compound (113 mg, 83%). j H-NMR (500MHz, CDC13) d 7.82 (two d, 1H), 7.54 (m, I 1 H), 7; .38 (m, 1H), 7.24-7.18 (m, 3H), 7.09-7.02 (m, 1H), 5.54-5.44 (m, 2H), 5.21-4.71 (m, 3H), 3.79 (m, 1H), 2.90-2.56 (m, 2H), 2.16 (m, 1H), 1.73 (m, 1H), 1.41 & 1.38 (two d, 9H), 0.96 (m, 3H) Example 18) Acid 3-. { 2- [2- (2-Chloro-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyrylamino} -5-fluoro-4-oxo-pentanoic The compound of Preparation 18-2) (103 mg, 0.29 mmol) was reacted according to the same procedure as Example 2) to give the title compound] (74 mg, 81%).; 1H-NMR (500MHz, DMS0-d6) d 8.63 (br, 1H), 7.91 (m, 1H), 7.45-7.25 (m, 4H), 7.00 (m, 1H), 5.32 (m, 2H), 5.30- 4.60 (br, 2H), 4.57 & 4.50 (two br m, 1H), 3.69 (m, 1H), 2.70- 2.50 (b | r, 2H), 1.77-1.65 (m, 2H), 0.84 (m, 3H) j! Preparation 19-1) Ethyl 2- [2- (3-chloro-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyric acid ethyl ester The compound of Preparation 6-6) ( 98 mg, 0.466 mmol) ^ 1-bromomethyl-3-chlorobenzene (127 mg, 1.3 eq, Aldrich) were reacted according to the same procedure as Preparation 2-1) to give the title compound (115 mg, 74%). "" "H-NMR (500MHz, CDC13) d 7.74 (d, 1H), 7.38 (s, 1H), 7.28-7.21 (m, 3H), 7.18 (d, 1H), 5.32-5.22 (ABq, 2H) , 4.21-4.10 (m, 2H), 3.84 (t, 1H), 1.99-1.75 (two m, 2H), 1.20 (t, 3H), 0.94 (t, 3H) Preparation 19-2) l Tert-butyl ester 3- {2- [2- (3-Chloro-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyrylamino} -5-fluoro-4-oxo- The compound of Preparation 19-1) (115 mg, 0.343 mmol) was reacted according to the same procedure as Preparation 3-5) to give the title compound (130 mg, 77%). -NMR (500MHz, CDC13) d 7.80 (m, 1H), 7.54 (d, 1H), 7.38 (d, 1H), 7.30-7.23 (m, 3H), 7.18 (m, 1H), 5.31-5.25 (m, _ »H) ', 5.21-4.71 (m, 3H), 3.76 (m, 1H), 2.91-2.62 I (m, 2H), 2.14 (m, 1H), 1.69 (m, 1H), 1.43 & 1.39 (two d, 9H), 0.96 (m, 3H) Example 19)! Acid 3-. { 2- [2- (3-chloro-benzyl) -3-OXO-2, 3-dihydro-pyridazin-4-yl] -butyrylamino} -5-fluoro-4-oxo-pentanoic , The compound of Preparation 19-2) (120 mg, 0.243 I mmol) was reacted according to the same 1 I procedure as Example 2) to give the title compound) (87 mg, 82%). 1H-NR (500MHz, DMSO-d6) d 8.62 (br, 1H), 7.89 (m, I 1 H), 7! .32-7.30 (m, 4H), 7.20 (m, 1H), 5.28-5.18 (m, 2H), 5.20- .60 (b | r, 2H), 4.58 & 4.50 (two br m, 1H), 3.66 (m, 1H), 2.70-2.50 (bt, 2H), 1.77-1.58 (m, 2H), 0.84 (m, 3H)! Preparation 20-1) Ethyl 2- [2- (3-bromo-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyric acid ethyl ester j The compound of Preparation 6-6) (100 mg, 0.48 mmol) and l-bromo-3-bromomethylbenzene (154 mg, 1.3 eq, Aldrich) were reacted according to the same procedure as Preparation 2-1) to give the title compound (102 mg, 54%). I, XH NMR (500MHz, CDCI3); d 0.95 (t, 3H), 0.96 (t, 3H), 1.78-1.95 (m, 2H), 3.85 (t, 1H), 4.15 (m, 2H), 5.27 (q, 2H), 7.17-7.45 (m , 5H), 7.54 (s, 1H), 7.75 (d, 1H) Preparation 20-2) j 3-tert-butyl ester. { 2- [2- (3-Bromo-benzyl) -3-yl) -2,3-dihydro-pyridazin-4-yl] -butyrylamino} -5-fluoror4-oxo-pentanoic acid 1 The compound of Preparation 20-1) (100 mg, 0.254 mmol) was reacted according to the same procedure as Preparation 3-5) to give the compound of the tirulo (120 mg, 88%). XH NMR (500MHz, CDCl 3); d 0.96 (m, 3H), 1.41 (d, 9H), i 1.69 (m, 1H), 2.13 (m, 1H), 2.60-2.91 (m, 2H), 3.76 (m, 1H), 4. 77 (mJ 1H), 5.01 (m, 2H), 5.29 (m, 2H), 7.18 (m, 2H), 7.30-7.45 (m, 2H), 7.52 (m, 2H), 7.80 (m, 1H) Example 20) 1 Acid 3-. { 2- [2- (3-bromo-benzyl) -3-OXO-2, 3-dihydro-pyridazin-4-yl] -buyrylamino} -5-fluoro-4-oxo-pentanoic The compound of Preparation 20-2) (80 mg, 0.15 mmol) was reacted according to the same I procedure as Example 2) to give the title compound i (59 mg, 81%). lti NMR (500MHz, CDCI3); d 0.96 (m, 3H), 1.68 (m, 1H), 1 2.06 (m, 1H), 2.50-3.16 (m, 2H), 3.84 (m, 1H), 4.77 (m, 3H), 5.29 (mj 2H), 7.19-7.52 (m, 6H), 7.91 (m, 1H) i Preparation 21-1) 2- [3-Oxo-2- (2-trifluoromethyl-benzyl) -2,3-dihydro-pyridazin-4-yl] -butyric acid ethyl ester I The compound of Preparation 6 -6) (104 mg, 0.50 mmol), j DIAD (diisopropyl azodicarboxylate, 151 mg, 1.5 eq), (2-trifluoromethyl-phenyl) -methanol (131 mg, 1.5 eq) and triphenylphosphine (261 mg, 2.0 eq) were dissolved in THF (6 mL) I i and they were frozen for 2 h at room temperature. The mixture was concentrated under reduced pressure and separated by column chromatography (30% EA / Hexane) to give the title compound (125 mg, 68%). t 1H-NMR (500MHz, CDC13) d 7.79 (d, 1H), 7.67 (d, 1H), i 7.44 (tj 1H), 7.36 (t, 1H), 7.26 (d, 1H), 6.97 (d, 1H) ), 5.62-5.54 (ABq, 2H), 4.21-4.12 (m, 2H), 3.90 (t, 1H), 2.03-1.81 (two m, 2H) [1.22 (t, 3H), 0.97 (t, 3H) Preparation 21-2) I Tert-butyl ester of 5-fluoro-4-oxo-3- acid. { 2- [3-Oxo-2- (2-trifluoromethyl-benzyl) -2, 3-dihydro-pyridazin-4-yl] -butyrylamino} pentanoic The compound of Preparation 21-1) (125 mg, 0.34 mmol); was reacted according to the same procedure as Preparation 3-5) to give the title compound (48 mg, 27%). XH-NMR (500MHz, CDC13) d 7.83 (two d, 1H), 7.68 (m, 1H), .51-7.44 (m, 2H), 7.36 (d, 1H), 7.23 (d, 1H), 7.00- 6.92 (dbs d, 1H), 5.69-5.51 (m, 2H), 5.21-4.73 (m, 3H), 3.78 (m, 1H), 2.90-2.58 (m, 2H), 2.16 (m, 1H), 1.75 (m, 1H), 1.37 (m, 9H), Example 21) I 5-Fluoro-4-oxo-3 acid. { 2- [3-Oxo-2- (2-trifluoromethyl-benzyl) -2, 3-dihydro-pyridazin-4-yl] -butyrylamino} -pentanoic The compound of Preparation 21-2) (48 mg, 0.092 I mmol): was reacted according to the same procedure as Example 2) to give the title compound! (37 mg, 86%). 1H-NMR (500MHz, CDC13) d 7.92 (dd, lH), -7.70 (d, 1H), 7.60 (bs, 1H), 7.45 (t, -1H), 7.39 (t, 1H), 7.35 (m, 1H), 6.95 (d, 1H), 5.64-5.51 (m, 2H), 4.77-4.35 (m, 3H), 3.84 (m, 1H), 3.06- 2.90 (mi, 1H), 2.68-2.58 (m, 1H), 2.12 (m, 1H), 1.74 (m, 1H), i 0.97 (t, 3H) I Preparation 22-1) Ethyl 2- [3-oxo-2- (3-trif) lucrimethylbenzyl ethyl ester ) -2, 3-dihydro-pyridazin-4-yl] -butyric The compound of Preparation 6-6) (100 mg, 0.48 mmol),: DIAD (diisopropyl azodicarboxylate, 192 mg, 2.0 eq), (3- trifluoromethyl-phenyl) -methanol (168 mg, 2.0 eq) and triphenylphosphine (312 mg, 2.5 eq) were dissolved in THF (6 mL) and stirred for 2 h at room temperature. The mixture was concentrated under reduced pressure and separated by column chromatography (30% EA / Hexane) to give the title compound (158 mg, 90%). I 1 H-NMR (500 MHz, CDC 13) d 7.76 (d, 1 H), 7.65 (s, 1 H), 7. 60 (d, 1H), 7.53 (d, 1H), 7.43 (t, 1H), 7.20 (d, 1H), 5.40-? 5.30 (A &q, 2H), 4.20-4.08 (m, 2H), 3.85 (t, 1H), 2.01-1.76 (two m, 2H) | 1.19 (t, 3H), 0.94 (t, 3H) Preparation 22-2) ^ 5-Fluoro-4-oxo-3-tert-butyl ester. { 2- [3-Oxo-2- ^ 3-trifluoromethyl-benzyl) -2, 3-dihydro-pyridazin-4-yl] -i-butyrylamino} pentanoic acid The compound of Preparation 22-1) (157 mg, 0.43 mmol) was reacted according to the same procedure as Preparation 3-5) to give the title compound (93 mg, 41%). 1H-NMR (500MHz, CDC13) d 7.80 (two d, 1H), 7.65 (two is, 1H) ', 7.60 (m, 1H), 7.52 (m, 2H), 7.44 (m, 1H), 7.18 (two d, 1H), 5i.42-5.33 (m, 2H), 5.18-4.71 (m, 3H), 3.74 (m, 1H), 2.90-2.60 (m, 2H), 2.12 (m, 1H), 1.68 ( ra, 1H), 1.42 & 1.38 (two s, 9H), 0.94 (m, 3H) j Example 22) 5-Fluoro-4-oxo-3 acid. { 2- [3-oxo-2- (3-trifluoro-j methyl-benzyl) -2, 3-dihydro-pyridazin-4-yl] -butyrylamino} -pentanoic The compound of Preparation 22-2) (93 mg, 0.18 mmol) i was reacted according to the same procedure as Example 2) to give the title compound j (75 mg, 90%). 1H-NMR (500MHz, CDC13) d 7.90 (dd, 1H), 7.65 (s, 1H), 7.57 (m! 2H), 7.45 (t, 1H), 7.32 (m, 1H), 5.37 (m, 2H) , 4.86-4.35 (m | 3H), 3.84-3.96 (m, 1H), 3.13-2.92 (m, 1H), 2.70-2.59 (m, 1H), 2.08 (m, 1H), 1.69 (ra, 1H) , 0.96 (t, 3H) Preparation 23-1)! 2,6-Dichlorobenzoate of (3S) -3-. { [(benzyloxy) -carbonyl] amino) -5- (tert-butoxy) -2-hydroxy-5-oxopentyl An N-benzyloxycarbonyl ^ -t-butyl-aspartic acid (5.03 g, 15.6 mmol) and NMM (1.90 mL, 17.1 mmol) were added anhydrous tetrahydrofuran (60 mL) under a nitrogen atmosphere, which was maintained at -15 ° C. Isobutylchloro formate (2.12 mL, 16.3 mmol) was added and the mixture was stirred I lasted approximately 20 min. To the reaction mixture kept at 0 ° C was added zometane-ether dia solution (synthesized from 2.0 eq of l-methyl-3-nitro-l-nitroso-guanidine, 60 mL), which was then stirred for 30 min. at 0 ° C to give the diazoketone derivative. 30% HBr / AcOH (6.42 ml, 2.0 eq) was added thereto at 0 ° C and stirred for 30 min. The reaction mixture was extracted with ethyl acetate, washed with water, twice with hydrogen carbonate solution aqueous, saturated solution clorurc aqueous sodium sodium, dried (Na2S04 anhydrous) and concentrated under reduced pressure to give the derivative of bromomethyl ketone (6.4 g). Derivative bromomethyl ketone (4.36 g) and 2-, 6-ditlorobenzoico (2.28 g, 1.1 eq) were dissolved in dimethylformamide (18 mL), KF (1.58 g, 2.5 eq) was added thereto 1 and the mixture was stirred for 2 has room temperature. The residue obtained by concentrating under reduced pressure was extracted with ethyl acetate, washed with water, twice with saturated aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, anhydrous Na2SO4 was dried) and dried. concentrated under reduced pressure to give the 2,6-dichlorobenzoxymethyl ketone derivative. This compound was dissolved in methanol (20 mL) and reacted by adding NaBH solution (412 mg) -methanol (40 mL). The mixture | The reaction mixture was heated slowly to room temperature for 2 h. The reaction was stopped by acetic acid. The reaction mixture was distilled under reduced pressure to remove methanol, extracted with ethyl acetate (50 mL x 2), washed with water and sodium chloride solution! aqueous, dried (a2 S04 anhydrous), concentrated under reduced pressure and separated by column chromatography (ethyl acetate-hexane, 1: 5) to give 4.80 g (86%) of the title compound. 1 H-NMR (400 MHz, CDC13) d 7.3-7.2 (m, 8H), 5.9 (m, 1H), 5j.2 (m, 4H), 4.7 (m, 1H), 2.9 (m, 1H), 2.7 (m, 1H), 1.4 (s, 9H) i j Preparation 23-2) 2, 6-Dichlorobenzoate of (3S) -3-amino-5- (tert-butoxy) -2-hydroxy-5-oxopentyl The compound of Preparation 23-1) (4.80 g, 9.37 mmol ) was dissolved in EtOH and subjected to debenzyloxycarbonylation (Pd / C) under a hydrogen balloon for 40 min to give 3.47 g (98%) of the title compound! ^ -NMR (400 MHz, DMS0-d6) d 8.2 (br, 2H), 7.6-7.5 (m, 3H), 6l (r 1H), 4.4-3.9 (m, 3H), 3.0-2.6 (m , 2H), 1.4 (s, 9H) Preparation 23-3) Ester (S) -4-tert-butoxycarbonyl-3-. { 2- [2- (2-tert-Butyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyrylamino} 2, 6-dichloro-benzoic acid-2-oxo-butylic The compound of Preparation 6-8) was hydrolyzed according to the same procedure as Preparation 2-3) to give the carboxylic acid derivative. A mixture of this carboxylic acid derivative (100 mg, 0.304 mmol), the compound of Preparation 23-2) (151 mg, 1.2 eq) and HATU (337 mg, 1.3 eq) was cooled to 0 ° C, was added triethylamine (0.17 mL, 4.0 eq) thereto in DMF solvent (4 mL) and the mixture was reacted for 1 h. The solvent was distilled under reduced pressure. The residue was extracted with ethyl acetate (30 mL x 2), washed with water, aqueous sodium hydrogen carbonate solution and sodium chloride solution. aqueous) was dried (anhydrous Na 2 SO 4) and concentrated under reduced pressure i to give (S) -4-tert-butoxycarbonyl-3-ester. { 2- [2- (2-tert-Butyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyryl-amino} -! - 2,6-dichloro-benzoic acid 2-hydroxy-butyl ester. To this compound and the Dess-Martin reagent (260 mg, 2.0 eq) was added anhydrous dichloromethane (4 mL), which was then stirred for 0.5 h at room temperature. The reaction was stopped with isopropyl alcohol (1 mL). The solid was removed I by celite filtration under reduced pressure and extracted, with ethyl acetate (20 mL x 2). The extract was washed with agiha, saturated aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried i (Na2SO4, anhydrous) and concentrated under reduced pressure. The residue was separated by column chromatography (20-25% ethyl acetate-hexane) to give 163 mg (78%) of the title compound. , XH-NMR (500MHz, CDC13) d 7.84 (m, 1H), 7.62 (m, 1H), 7.43 (t, ¡1H), 7.34-7.25 (m, 4H), 7.16 (m, 1H), 7.06 ( t, 1H), 6.83-6.7 (two d, 1H), 5.86-5.52 (m, 2H), 5.22- .81 (m, 3H), 3.86 (m, (1H), 2.89-2.62 (m, 2H) , 2.02 (m, 1H), 1.75 (m, 1H) "1.49 &; 1.48 (two s, 9H), 1.41 & 1.37 (two s, 9H), 0.99 (m,! 3H) Example 23-1) and 23-2) Ester (S) -3-. { (R) -2- [2- (2-tert-Butyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl} -butyrylamino} -4-carboxy-2-oxo- butyl 2-6-dichloro-benzoic acid and i-Ester (S) -3-. { (S) -2- [2- (2-tert-Butyl-benzyl) -3-oxo-i, 2,3-dihydro-pyridazin-4-yl} -butyrylamino} 2-6-dichloro-benzoic acid-2-carboxy-2-oxo-butyl ester 1 The compound of Preparation 23-3) (159 mg, 0.29 mmol) was reacted according to the same procedure as Example 2) to give the compound of I title was a mixture of two diastereomers, which was then separated by Prep-TLC (70% EtOAc / Hexane) to give 62 mg (42%) and 50 mg (34%) of each diastereomer. The compound with more, low polarity on TLC was assigned as Example 23-1 and, the compound with higher polarity as Example 23-2, but its specific diastereomeric forms were not identified. Compound with lower polarity: 1H-NMR (500MHz, DMSO-dg) 1 d 8.78 (br, 1H), 7.93 (m, 1H), 7.56-7.52 (m, 3H), 7.40 (m, ??), 7.34 (t, 1H), 7.11 (m, 1H), 7.05 (m, 1H), 6.67 (d, 1H), 5.98-5.42 (ABq, 2H), 5.30-.60 (br m, 3H), 4.58 & 4.50 (two i br m, 1H), 3.72 (m, 1H), 2.70-2.50 (br, 2H), 1.82-1.63 (m, 2H), 1. 40 (m> 9H), 0.85 (m, 3H) (Example 23-1) Compound with higher polarity: XH -NMR (500MHz, DMSO-dk) d 8.74 (br, 1H), 7.93 (m, 1H) , 7.57-7.51 (m, 3H), 7.40 (d, 1H), 7.34 (d, 1H), 7.11 (m, 1H), 7.02 (m, 1H), 6.67 (d, 1H), 5.56-5.43 (ABq , 2H), 5.26-5.00 (br m, 2H), 4.72 (m, 1H), 3.70 (m 1H), 2.76-2.50 (br, 2H), 1.82-1.63 (m, 2H), 1.38 (s, 9H ), 0.85 (t, 3H) (Example 23-2) Preparation 24-1) (3S) -3-Amino-4-hydroxy-5- (2,3,5,6-tetrafluoro-phenoxy) pentanoate of ter- Butyl N-benzyloxycarbonyl- -t-butyl-aspartic acid (17.9 g, 55.5 mmol) and 2, 3, 5, 6-tetrafluorophenol were reacted according to the same procedure as Preparation i-1 and 23-2 ) to give 13.2 g (68%) of the title compound. 1 H-NMR (400 MHz, DMSO-d 6) d 8.2 (br, 2 H), 7.6-7.5 (m, I 1 H), 5.9 (m, 1 H), 4.3-4.1 (m, 3 H), 3.6 (m, 1 H), 2.7 (m, 1 H), 1.4 (s, 9 H) Preparation 24-2) I Ester tert-butyl of acid (S) -3-. { (R) -2- [2- (2-tert-Butyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyryl-amino} ^ 4-oxo-5- (2,3,5,6-tetrafluoro-phenoxy) -pentanoic acid and; 'Ester-butyl acid ester (S) -3-. { (S) -2- [2- (2-tert-Butyl-lenyl) -3-oxo-2,3-di-idro-pyridazin-4-yl] -b-triethylamino} ^ · 4 - ??? - 5- (2,3,5,6-tetrafluoro-phenoxy) -pentanoic acid The compound of Preparation 6-8) (104 mg, 0.29 mol) was hydrolyzed according to the same procedure as Preparation 2-3) to give the carboxylic acid derivative. A mixture of this carboxylic acid derivative (95 mg, 0.29 mmol), the compound of Preparation 24-1) (113 mg, l.j2 eq) and HATU (143 mg, 1.3 eq) was cooled to 0 ° C, triethylamine (0.16 mL, 4.0) was added. eq) to the same in DMFj solvent (5 mL) and the mixture was reacted for 2 h. The solvent was distilled under reduced pressure. The residue was extracted with ethyl acetate (30 mL x 2), washed with water, Aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried (anhydrous Na 2 SO 4), concentrated under reduced pressure and preliminarily purified by Prep-TLC (500% EA / Hexane) to give 172 mg (89%) of tert-butyl ester of (S) -3- acid. { 2- [2- (2-tert-Butyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyryl-amino} j- -hydroxy-5- (2,3,5,6-tetrafluoro-phenoxy) -pentanoic acid. To this compound and the Dess-Martin reagent (220 mg, 2.0 eq) was added anhydrous dichloromethane (4 mL), which was then i stirred 'for 1 h at room temperature. The reaction was stopped by isopropyl alcohol (1 mL). The solid was removed by celite filtration under reduced pressure and extracted with ethyl acetate (20 mL x 2). The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried (anhydrous Na 2 SO 4) and concentrated under reduced pressure. The residue was purified by Prep-TLC (30% EA / Hexane) i to give 74 mg (38%) of the titre diastereomer with lower polarity and 67 mg (35%) with higher polarity. 'Diastereomer with lower polarity: 1H-NMR (500MHz ', CDC13) d 7.83 (d, 1H), 7.59 (d, 1H), 7.42 (d, 1H), i 7.22 (d, | 1H), 7.17 (t, 1H), 7.06 (t, 1H) , 6.76 (m, 1H), 6.73 (d, 1H), 5.65 (Abq, 2H), 5.19-5.02 (Abq, 2H), 4.75 (m, 1H), 3.81 (dd, 1H), 2.'76 ( dd, 1H), 2.59 (dd, 1H), 2.19 (m, 1H), 1.73 (m, 1H), 1. 48 (s, 9H), 1.34 (s, 9H), 0.98 (t, 3H) I! Diastereomer with higher polarity: 1H-NMR (500MHzJ CDCI3) d 7.83 (d, 1H), 7.61 (d, 1H), 7.39 (d, 1H), 7. 23 (d, '??), 7.14 (t, 1H), 7.05 (t, 1H), 6.78 (d, 1H), 6.72 (m, 1H), 5.74-5.58 (Abq, 2H), 5.07 -4.83 ( Abq, 2H), 4.82 (m, 1H), 3.80 (dd, ¡1H), 2.89 (dd, 1H), 2.68 (d, 1H), 2.16 (m, 1H), 1.75 (m,! 1H), 1.48 (s, 9H), 1.39 (s, 9H), 0.96 (t, 3H) Example 24-1) and 24-2) I 1 Acid (S) -3-. { (R) -2- [2- (2-tert-Butyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyrylamino} -4-oxo-5- (2,3,5,6- tetrafluoro-phenoxy) -pentanoic acid and (S) -3- acid. { (S) -2- [2- (2-tert-Butyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyryl-amino} -4-oxo-5- (2,3,5,6-tetrafluoro-phenoxy) -pentanoic acid The compound with the lowest polarity prepared in the Preparabion 24-2) (74 mg, 0.11 mmol) was reacted according to the same procedure as Example 2) to give one of the title compounds (58 mg, 87%) which was assigned as Example 24 -1) . i, 1H-NMR (5001MHz, CDC13) d 7.91 (d, 1H), 7.43 (d, 1H), 7.39 (bs; 1H), 7.18 (t, 1H), 7.05 (t, 1H), 6.75 (m, 1H), 6.70 (d, 1H), 5.5 (s, 2H), 5.40-4.50 (m, 3H), 3.95 (m, 1H), 3.01 (m, 1H), 2.55 (m,, 1H) , 2.13 (m, 1H), 1.73 (m, 1H), 1.47 (s, 9H), 0.97 (t, 3H) (Example 24-1) I! The compound with higher polarity prepared in Preparation 24-2) (67 mg, 0.10 mmol) was reacted according to the same procedure as Example 2) to give the other of the title compounds (60 mg , 98%) which 1 was assigned as Example 24-2). 1H-NMR (500MHz, CDC13) d 7.91 (d, 1H), 7.42 (d, 1H), 7.31 (bs, 1H), 7.16 (t, 1H), 7.03 (t, 1H), 6.75 (m, 1H) , 6.70 (d, 1H), 5.65 (s, 2H), 4.89-4.03 (m, 3H), 3.76 (m, 1H), 2.99 (m, 1H), 2.70 (m, 1H), 2.12 (m, 1H) ), 1.75 (m, 1H), 1.48 (s, 9H), 0.97 (t, 3H) (Example 24-2) Preparation 25-1) Tert-butyl ester of (S) -3- acid. { 2- [2- (3-tert-Butyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyryl-amino} ^ 4-oxo-5- (2,3,5,6-tetrafluoro-phenoxy) -pentanoic The compound of Preparation 7-2) (135 mg, 0.38 mmol) was reacted according to the same procedure as the Preparation 24-2) to give the title compound (198 mg, 79%). 1 1H-NMR (500MHz, CDC13) d 7.79 (two d, 1H), 7.63 (m, 1H), 7.42 (two s, 1H), 7.32-7.14 (m, 4H), 6.73 (m, 1H), 5.43 -5.21 (m 2 H), 5.20-4.71 (m, 3 H), 3.77 (m, 1 H), 2.93-2.59 (m, 2 H), 2.15 (m! 1 H), 1.69 (m, 1 H), 1.43 & 1.40 (two s, 9H), 1.29 (s, 9H), 0.95 (m, 3H) Example 25-1) and 25-2) (S) -3- acid. { (R) -2- [2- (3-tert-Butyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyrylamino} -4-oxo-5- (2,3,5,6-tetrafluoro-phenoxy) -pentanoic acid and (S) -3-. { (S) -2- [2- (3-tert-Butyl-benzyl) -3-oxo-1,2-, 3-dihydro-pyridazin-4-yl] -butyrylamino} -4-oxo-5- (2,3,5,6-tetrafluoro-phenoxy) -pentanoic acid ; The compound of Preparation 25-1) (75 mg, 0.11 mmol) 1 was reacted according to the same procedure as Example 2) to give the title compound as a mixture of two diastereomers, which was then separated by Prep-TLC (70% EtOAc / Hexane) to give 31 mg (44%) of a diastereomer with lower polarity (Example 25-1) and 33 mg (48%) of a diastereomer with higher polarity (Example 25) -2). Diastereomer with lower polarity: H-NMR (500MHz, DMSO-de) d 8.70 (m, 1H), 7.87 (d, 1H), 7.50 (m, 1H), 7.30 (s <1H), 7.24 (d, 2H), 7.18 (m, 1H) , 6.97. { m, 1H), 5.24-5.03 (m, 4H), 4.64-4.52 (m, 1H), 3.68 (m, 1H), 2.68-2.58 (m, 2H), 1.73 (m, 1H), 1.63 (m , 1H), 1.19 (8, 9H), 0.82 (m, 3H) (Example 25-1) 1 Diastereomer with higher polarity: H-NMR (500MHz, DMSO-d6) d 8.66 (m, 1H), 7.87 (d, 1H), 7.50 (m, 1H), 7. 30 (s, 1H), 7.25 (two d, 2H), 7.16 (m, 1H), 6.96 (m, 1H), 5.23-4.90 (m ,: 4H), 4.63-4.54 (m, 1H), 3.68 ( m, 1H), 2.68-2.50 (m, 2H), 1.73 (m, 1H), 1.63 (m, 1H), 1.19 (s, 9H), 0.82 (m, 3H) (Example 25-2) Preparation 26-1) 1-Methyl ester ester hydrochloride 4-tert-butyllacid of (S) -2-amino-succinic acid A Cbz-Asp (0-ter-Bu) -OH.H20 (5.00 g, 14.6 mmol) and K2C03 (4.05 g, 2.0 eq) were added DMF (100 mL) and Mel (2.74 mL, 3 jeq), which was then stirred for 2-3 h at room temperature. The solvent was distilled under reduced pressure. The residue was extracted with ethyl acetate (100 mL x 2), washed with water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried (anhydrous Na 2 SO 4) and concentrated under reduced pressure. The residue was purified by column chromatography (30% ethyl acetate / hexane) to give (S) -2-benzyloxycarbonylamino-succinic acid-1-methyl ester of butyl ester in a stoichiometric yield. This compound was dissolved in MeOH (100 mL), c-HCl (1.1 mL, 1.0 eq) was added and the desbenzyloxycarbonylation (Pd / C) was carried out for 40 min under a hydrogen balloon, giving 3.28 g ( 96%) of the title compound. Preparation 26-2) 1-Methyl ester of 4-tert-butyl ester of i (S) -2- acid. { 2- [2- (2-tert-Buryl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyrylamino} -succinic The compound of Preparation 6-8) was hydrolyzed from i agreed with the same procedure as Preparation 2-3) to take the carboxylic acid derivative. A mixture of this icarboxylic acid (938 mg, 2.86 mmol), the compound of the Preparation 26-1) (753 mg, 1.1 eq) and HATU (1.41 g, 1.3 eq) was cooled, at 0 ° C, triethylamine (2.00 mL, 5.0 eq) was added thereto in DMF solvent (18 mL) and the mixture was reacted for 1 h at room temperature. The solvent was distilled1, under reduced pressure. The residue was extracted with ethyl acetate (50 mL x 2), washed with water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried (anhydrous a 2 SO 4) and concentrated under reduced pressure. The residue was purified by column chromatography (50% ethyl acetate-hexane) to give 1.24 g (84%) of the title compound. i XH-NMR (400MHz, CDC13) d 7.84 (dd, 1H), 7.48 (d, 1H), 7. 41-7.3j2 (dd, 1H), 7.30 (d, 1H), 7.23 (m, 1H), 7.14 (m, 1H), 6.92-6.8.3 (dd, 1H), 5.76-5.65 (m, 2H) , 4.82 (m, 1H), 3.91 (m, 1H), 3.76, 3.68 (two s, 3H), 2.92-2.63 (m, 2H), 2.19 (m, 1H), 1.76 (m, ¡LH), 1.55 (s, 9H), 1.46, 1.42 (two s, 9H), 1.02 (m, 3H). 1 Preparation 26-3) Tert-butyl ester of (S) -5-bromo-3- acid. { 2- [2- (2-tert-Butyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyrylamino} -4-oxo-pentanoic acid 1 The compound of Preparation 26-2) (1.24 g, 2.41 mmol) was hydrolyzed according to the same procedure as i Preparation 2-3) to give the carboxylic acid derivative (1.15 g, 95%). To this carboxylic acid derivative (1.15 g, 2. 30 mmol) and N M (0.28 mL, 2.53 mmol) was added anhydrous tetrahydrofuran (20 mL) under a nitrogen atmosphere, which was maintained at 0 ° C. Isobutyl formate was added (0.31 mL, 2.42 mmol) and. The mixture was stirred for approximately 30 min. Diazomethane-ether solution was added to the reaction mixture maintained at 0 ° C.

I (synthesized from 4.0 eq of l-methyl-3-nitro-l-nitroso-guanidiha, 40 mL), which was then stirred for 4 h at 0 ° C to give the diazoketone derivative. 30% HBr / AcOH (1.02 mL, 2.0ieq) was added thereto at 0 ° C and stirred for 30 min. The reaction mixture was extracted with ethyl acetate, washed with water, twice with saturated aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried (anhydrous Na 2 SO 4) and concentrated under pressure ( reduced to give the bromomethylketone derivative (1.30 g, 98%) This compound was used in the next reaction without further purification.1H-NMR (500MHz, CDC13) d 7.84 (dd, 1H), 7.63-7.58 ( dd, 1H), 7.43 (d, 1H), 7.25-7.17 (m, 2H), 7.09 (m, 1H), 6.83- i 6.75 (dd, 1 1H), 5.74-5.62 (m, 2H), 4.91, 4.82 ( two m, 1H), 4.12-3.93 (m, '2H), 3.79 (m, 1H), 2.91-2.60 (m, 2H), 2.17 (m, 1H), 1.74 (m, 1H), 1.49 (s, 9H), 1.40, 1.36 (two s, 9H), 0.97 (m, 3H). i Preparation 26-4) Ter-butyl ester of (S) -3- acid. { 2- [2- (2-tert-Butyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyryl-amino} r4-oxo-5- (2,3,6-trifluoro-phenoxy) -pentanoic The compound of Preparation 26-3) (100 mg, 0.17 mmol) and 2,3,6-trifluorophenol (31 mg, 1.2 eq) were dissolved in dimethylformamide (2 mL), KF (25 mg, 2.5 eq) was added thereto, and the mixture was stirred for 4 h at room temperature. The residue obtained by concentration under reduced pressure was extracted with ethyl acetate, washed with water, twice with aqueous sodium hydrogen carbonate solution, saturated and aqueous sodium chloride solution, dried (anhydrous Nia2SO4) and concentrated under reduced pressure. The residue was purified by Prep-TLC (70% ethyl acetate / hexane) to give 77 mg (69%) of the title compound. , XH-NMR (500MHz, CDC13) d 7.82 (m, 1H), 7.56 (m, 1H), 7.42 (t, < 1H), 7.23 (t, 1H), 7.16 (m, 1H), 7.06 (m , 1H), 6.82-6.73 (m, '3H), 5.76-5.55 (m, 2H), 5.10-4.78 (m, 3H), 3.82 (m, 1H), 2. 94-2.6'p (m, 2H), 2.16 (m, 1H), 1.73 (m, 1H), 1.46 (s, 9H), 1.39.1.3'd (two s, 9H), 0.95 (m, 3H) . ! Example 26-1) and 26-2) 1 (S) -3- acid. { (R) -2- [2- (2-tert-Butyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyrylamino} -4-oxo-5- (2,3,6-trifluoro-phenoxy) -pentanoic acid, and (S) -3- acid. { (S) -2- [2- (2-tert-butyl-benzyl) -3-oxo- 2, 3-dihydro-pyridazin-4-yl] -butyrylaram} -4-oxo-5- (2,3,6-trifluoro-phenoxy) -pentanoic acid The compound of Preparation 26-4) (77 mg, 0.12 mmol) i was reacted accordingly! procedure as Example 2) to give the title compound as a mixture of two diastereomers, which was then separated by Prep-TLC (50% ethyl acetate / hexane) to give 24 mg (34%) of a diastereomer with lower polarity (Example 26-1) and 17 mg (24%) of a diastereomer with higher polarity (Example 26-2). j Diastereomer with lower polarity: 1H-NMR i (500MHz, CDC13) d 7.89 (d, 1H), 7.43 (d, 1H), 7.30 (m, 1H), 7.18 (t, 1H), 7.05 (t, 1H) ), 6.83 (m, 2H), 6.71 (d, 1H), 5.67- 5.63 (m, 2H), 4.82-.10 (m, 3H), 3.84 (m, 1H), 2.86 (m, 1H), 2. 52 (m |, 1H), 2.16 (m, 1H), 1.73 (m, 1H), 1.48 (s, 9H), 0.95 (t, 3H). . Diastereomer with higher polarity: 1H-NMR (500MH | z, CDCI3) d 7.90 (d, 1H), 7.41 (d, 1H), 7.32 (m, 1H), 7. 15 (t, 1H), 7.02 (t, 1H), 6.79 (m, 2H), 6.70 (d, 1H), 5.63 (m, 2H), .89-4.05 (m, 3H), 3.90 (m, 1H ), 3.05 (m, 1H), 2.69 (m, 1H), 2.12 (m, 1H), 1.73 (m, 1H), 1.47 (s, 9H), 0.96 (m, 3H). Preparation 27) Tert-butyl ester of (S) -3- acid. { 2- [2- (2-tert-Butyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyryl-amino} -5- (2,6-difluoro-phenoxy) -4-oxo-pentanoic acid The compound of Preparation 26-3) (100 mg, 0.17 mmol) and 2,6-difluoro-phenol (27 mg, 1.2 eq) is dissolved in dimetijlformamide (2 mL), KF (25 mg, 2.5 eq) was added thereto and the mixture was stirred for 4 h at room temperature. The residue obtained by concentration under reduced pressure was extracted with ethyl acetate, washed with water, twice with saturated aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried | Na2SC > 4 anhydrous) and concentrated under reduced pressure. The residue was purified by Prep-TLC (70% ethyl acetate / hexane) to give 77 mg (71%) of the title compound; i. S 1 H-NMR (500 MHz, CDC 13) d 7.79 (m, 1 H), 7.54 (m, 1 H), 7. 41 (m, 1H), 7.23 (m, 1H), 7.16 (m, 1H), 7.05 (m, 1H), 6.92-6.72 (m, 4H), 5.76-5.52 (m, 2H), 5.02-4.73 ( m, 3H), 3.84 (m, 1H), 2. 97-2¡.62 (m, 2H), 2.15 (m, 1H), 1.71 (m, 1H), 1.48 (s, 9H), i 1.40, 1.34 (two s, 9H), 0.96 (m, 3H) . Example 27-1) and 27-2) Acid (S) -3-. { (R) -2- [2- (2-tert-Butyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyrylamino) -5- (2,6-difluoro-phenoxy) -4-oxo-pentanoic acid (S) -3-. { (S) -2- [2- (2-tert-Butyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyrylamino} -5- (2,6-difluoro-phenoxy) -4-oxo-pentanoic acid The compound of Preparation 27) (75 mg, 0.11 mmol) was reacted according to the same procedure as Example 2) to give the title compound as a mixture of two diastereomers, which was then separated; by Prep-TLC (50% EtOAc / Hexane) to give 25 mg (36%) of a diastereomer with lower polarity (Example 27-1) and 24 mg (35%) of a diastereomer with higher polarity (Example 27-2). Diastereomer with lower polarity: H-NMR (500MH | z, CDC13) d 7.88 (d, 1H), 7.43 (d, 1H), 7.28 (m, 1H), 7.18 (t !, 1H), 7.05 (t, 1H), 6.97 (m, 1H) , 6.87 (t, 2H), 6.71 (d, 1H), 5.67-5.63 (m, 2H), 4.77-4.10 (m, 3H), 3.82 (m, 1H), 2.83 (m, 1H), 22.51 (m, 1H), 2.14 (m, 1H), 1.71 (m, 1H), 1.48 (s, 9H), i 0.95 (t ', 3H)' Diastereomer with higher polarity, and: 1H- NMR (500MH'z, CDCI3) d 7.87 (d, 1H), 7.41 (d, 1H), 7.29 (m, 1H), I 7.16 (t ', 1H), 7.03 (t, 1H), 6.93 (m, 1H), 6.83 (t, 2H), 6.72 (d, 1H), 5'.67-5.62 (m, 2H), 4.88-4.10 (m, 3H), 3.87 (m, 1H), 3.04 (m, 1H), 2.67 (m, 1H), 2.11 (m, 1H), 1.72 (m, 1H), 1.46 (s, 9H) , 0. 96 (t 3H). 1 Preparation 28) 1-Tertiary butyl ester of (S) -3- acid. { 2- [2- (2-tert-1-butyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyryl-amino} J5- (diphenyl-phosphinoyloxy) -4-oxo-pentanoic acid 1 The compound of Preparation 26-3) (100 mg, 0.17 mmol) and diphenylphosphinic acid (45 mg, 1.2 eq) were dissolved in dimethylformamide (2 mL), KF (25 mg, 2.5 eq) was added to the same j the mixture was stirred for 4 h at room temperature. The residue obtained by concentration under reduced pressure was extracted with ethyl acetate, washed with water, dbs. Times with aqueous sodium hydrogen carbonate solution, saturated and aqueous sodium chloride solution, dried (anhydrous N 2 SO 4). and concentrated under reduced pressure. The residue was purified by Prep-TLC (50% ethyl acetate / hexane) to give 80 mg (65%) of the title compound. : 1 1H-NMR (500MHz, CDC13) d 7.87-7.76 (m, 5H), 7.56-7.41 1 8 ??), 7.18-7.14 (m, 2H), 7.07 (m, 1H), 6.83-6.72 (dd, 1H), 5. 77-5 56 (m, 2H), 4.94-4.62 (m, 3H), 3.77 (m, 1H), 2.79-2.54 (m, 2H), 2 09 (m, 1H), 1.68 (m, 1H), 1.48 (s, 9H), 1.36 & 1.31 (two s, 9H), 0.89 (m, 3H). Example 28) Acid (S) -3-. { 2- [2- (2-tert-Butyl-benzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -butyrylamino} -5- (diphenyl-phosphonoyl-oxy) -4-p-pentanoic The compound of Preparation 28) (80 mg, 0.11 mmol) was reacted according to the same procedure as Example 2), concentrated under reduced pressure and separated by Prep-TLC (10% MeOH / CH2C12 ) to give 68 mg (91%) of the title compound as a mixture of two diastereomers. 1 H-NMR (500MHz, CDCl 3) d 7.80-7.71 (m, 5H), 7.52-7.40 (m, 7H), 7.20 (m, 1H), 7.15 (m, 1H), 7.04 (m, 1H), 6.75 (m, 1H), 5.72-5.49 (m, 2H), 4.76-4.10 (m, 3H), 3.84 (m, 1H), 2.93-2.54 (m, , 1.98 (m, 1H), 1.65 (m, 1H), 1.46 (s, 9H), 0.87-0.79 (m, SH). Experiment 1 Determination of the inhibitory effect of caspase Caspase-1 and caspase-8 known as cysteine proteases in the form of O 2 / ¾ were expressed, purified and activated by modifying a known method in Thornberry, NA et al., Nature, 1992, 356, 768. Thornberry, NA Methods in Enzymology, 1994, 244, 615. Walker, NPC et al., Cell, 1994, 78, 343 and caspase-9 was also purified by a similar method, and the inhibitory activity against them was tested. Briefly describing, the plO and p20 subunits (Thornberry, NA et al., Nature, 1992, 356, 768) were expressed in E. coli and purified by the nickel column and anion exchange chromatography to give caspase-1, caspasa-8 and caspasá-9. Fluorescent substrates AcYVAD-AFC for the caspase-1 thus obtained, AcDEVD-AFC for caspase-8 and AcLEHD-AFC for caspase-9, were used to determine the specific activity of the inhibitors synthesized. The enzyme reaction was carried out at 25 ° C with various concentrations of the inhibitors in buffer containing 50 mM HEPES (pH 7.50), 10% sucrose (w / v), 0.1% CHAPS (w / v) ), 100 mM NaCl, lmM EDTA and 10 mM DTT in the presence of 50 μM AcYVAD-AFC? for caspasa-1 10 nM, AcDEVD-AFC 5? μ? for caspasa-8 2.1 nM and AcLEHD-AFC 150 μ? for i caspasa-9 200 nM. The inhibitory constants Ki and Kobs of the I inhibitors were determined by measuring the reaction rate with the lapse of time using a spectrometer fluorescent and to obtain the initial proportion constant. Ki was calculated from the Lineweaver Burk and Kobs graph of the following Equation 1. [EcuaJion 1] i Kobs = -ln (1-At / A00) / t in which At means proportion of segmentation (%) in time! t, and Aoo means the maximum segmentation ratio I < %) · 'The GeminiXS Spectra MAX Fluorescent Spectrometer from Molecular Device Co was used. at the excitation wavelength of 405 nm and the emission wavelength of I 505 nm. The in vivo inhibitory activity of the inhibitors was determined by subjecting the Jurkat cells (ATCC TIB-152) to apoptosis using the Fas antibody (Upstate Biotech 05-201) and 1 to the detector changing the color according to the method j WST-I known in Francoeur AM and Assalian A. (1996) Biochemistry 3, 19-25 to observe the amount of Jurkat cells alive when the cells were treated by the inhibitor. The Spectra MAX 340 spectrometer from Molecular Device Co was used. at the absorbance wavelength of 440 nm. [Table ?] I I i Experiment 2 ii Therapeutic effect for induced liver injury or antibody against Fas in mouse i Step 1) Preparation of blood sample 1 Male Balb / c mice (6 weeks, Charles River Laboratory, Osaka, Japan) were kept under the conditions of 22 ° C, 55% relative humidity and light-dark cycle of 12 hor s. Food and water were supplied ad libitum. In a pyrogen-free phosphate buffer solution, the antibody against Fas (Jo2; BD pharmingen, San Diego, California) was dissolved, which was then injected into each mouse in the amount of 0.15 mg / kg through the vein of The tail. Immediately after injection of the Fas antibody, the vehicle (a mixture of PEG400: ethanol = 2: 1 was 20 times diluted 1 with phosphate buffer) where the test compound is dissolved or the vehicle alone was orally administered to the rats. After 6 hours of the administration of the drug; Blood samples were obtained from their hearts. Step 2: Determination of plasma aminotransferase activity Plasma PLT activity was determined for blood samples obtained in Stage 1 using the ALT assay kit (Asan Pharm. Co., Seoul, Korea) according to don the instruction of the manufacturer. The results showed that Fas antibody injection strongly I increases the activity of ALT in the plasma and the pruieba compounds inhibit the increased enzyme activity in a dose-dependent manner. Based on these results, the ED50 values of the test compounds were calculated using the Prism software from GraphPad Co. to give 0.001- ! FIELD OF INDUSTRIAL APPLICATION As shown by the previous results of the Experiments, the compound of the formula (1) of the present invention has an excellent inhibitory activity against i caspasa, and particularly exhibits a therapeutic effect in the animal model of the liver lesion induced by the Fas antibody. Therefore, the compound of formula (1) can be advantageously used for the treatment of various diseases and symptoms mediated by caspase.

Claims (12)

1. A compound of the formula [Formula 1] characterized in that i I) R1 represents H, C1-C5 alkyl, C3- (C2) cycloalkyl, aryl or a side chain residue of all natural amino acids, I

II) R 2 represents H, C 1 -C 5 alkyl, C 3 -C 10 cycloalkyl, aryl or a side chain residue of all natural amino acids, j III) R 3 represents H, C 1 -C 6 alkyl, hydroxy, C 1 alkoxy C5 or halogen, IV) R4 represents H, C1-C5 alkyl, C3-Cio cycloalkyl or aryl, 'V) R5 represents H, C1-C5 alkyl, C3-C] cycloalkyl or aryl; VI) R6 and R7 independently from each other represent H, C1-C5 alkyl, C3-Ci0 cycloalkyl or aryl, VII) X represents -CH2OR9 (R9 is C1-C5 alkyl, C3-Ci0 cycloalkyl or aryl) , -CH2OC (= 0) R10 (R10 is C1-C5 alkyl, C3-C10 cycloalkyl or aryl), -CH2-0P (-0) Rn2 (Ru is C1-C5 alkyl, C3 cycloalkyl) Ci0 or aryl), or -CH2-W (W

I is halogen) or pharmaceutically acceptable salt thereof. I 2. The compound according to claim 1, characterized in that R5 represents Ci- (5-substituted by substituted or unsubstituted C3-C10 cycloalkyl or substituted or unsubstituted aryl, or i represents substituted or unsubstituted aryl, or pharmaceutically acceptable salt thereof 3. The compound according to claim 2, characterized in that R5 represents alkyl

Of C1-C5 substituted by C3-C10 cycloalkyl which is not 1 substituted or substituted by one or more substituents i selected from the group consisting of C 1 -C 5 alkyl, hydroxy, C 1 -C 5 alkoxy and halogen, or by aryl which is unsubstituted or substituted by one or more substituents selected from the group which consists of C 1 -C 5 alkyl, hydroxy J, C 1 -C 5 alkoxy and halogen; or represents aryl that is unsubstituted or substituted by one or more substituents selected from the group consisting of C 1 -C 5 alkyl, hydroxy, C 1 -C 5 alkoxy and halogen, or pharmaceutically acceptable salt thereof. I. The compound according to claim 1, characterized in that ^ I) R1 represents a side chain residue of all natural amino acids, II) R2 represents C1-C5 alkyl, 107 i 1 III) 3 represents H, C 1 -C 5 alkyl, C 1 -C 5 alkoxy halogen, IV) R 4 represents H, V) R 5 represents C 1 -C 5 alkyl substituted by C 3 -C 10 cycloaicyl which is unsubstituted or substituted by one or more substituents selected from the group consisting of C 1 -C 5 alkyl, hydroxy, C 1 -C 5 alkoxy and halogen, or 1 by aryl which is unsubstituted or substituted by one or more substituents selected from the group consisting of C1-Q5 alkyl, hydroxy, C1-C5 alkoxy and halogen; or represents aryl that is unsubstituted or substituted by one or more substituents selected from the group consisting of C1-C51 alkyl, hydroxy, C1-C5 alkoxy and halogen, VI) R6 and R7 independently of each other represent H, , VII) X represents -CH2OR9 (R9 is C1-C5 alkyl, C3-C10 cycloaicyl or aryl), -CH2OC (= 0) R10 (R10 is Ci-Cg alkyl, C3-C10 cycloaicyl or aryl), or -CH2-W (W is

I halogen ',), or pharmaceutically acceptable salt thereof. The compound according to claim 1, characterized in that ', I) R1 represents -CH2COOH, 1 II) R2 represents C1-C5 alkyl,' 3 'III) R represents H, C1-C5 alkyl, alkoxy from 1 C1-C5 or halogen,

IV) R4 represents H,? V) R 5 represents C 1 -C 5 alkyl substituted by C 3 -C 10 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from the group consisting of C 1 -C 5 alkyl, hydroxy, C 1 -C 5 alkoxy and halogen, or by aryl which is unsubstituted or substituted by one or more substituents selected from the group consisting of C1-Q5 alkyl, hydroxy, C1-C5 alkoxy and halogen; or represents aryl that is unsubstituted or substituted by one or more substituents selected from the group consisting of C 1 -C 5 alkyl, hydroxy, C 1 -C 5 alkoxy and halogen, VI) R 6 and R 7 independently from each other represents H, VII) X represents -CH20- (2, 3, 5, 6-tetrafluoro-phenyl), -CH20- (2, 3, 6-trifluorophenyl), -CH20- (2,6-difluorophenyl), -CH20- (2, 6) -dichlorobenzoyl) or -CH2-F, or pharmaceutically acceptable thereof. | 6. 3-2- [2- (2-tert-Butyl-benzyl) -3-OXO-2, 3-dihydro-pyridazin-4-yl] -butyrylamino-5-fluoro-4-oxo-pentanoic acid or ',

7. 3-2- [2- (3-tert-Butyl-benzyl) -3-oxo-2,3-dihydro-f) iridazin-4-yl] -butyrylamino-5-fluoro-oxo-3-acid pentanoic <

8. A pharmaceutical composition for inhibiting caspase, characterized in that it comprises the compound as defined in any one of claims 1 to 7 or pharmaceutically acceptable salt thereof as an active ingredient 'together with a pharmaceutically acceptable carrier.

9. The composition according to claim 8, characterized in that it is to prevent inflammation and apoptosis.

10. The composition according to claim 8, characterized in that it is for the treatment or prevention of dementia, cerebral apoplexy, brain deterioration due to AIDS, diabetes, gastric ulcer, cerebral injury due to hepatitis, hepatic diseases induced by hepatitis, acute hepatitis. , fulminant hepatic failure, sepsis, rejection of organ transplantation, rheumatic arthritis, cardiac cell apoptosis due to ischemic heart disease or cirrhosis of the liver. (

11. The composition according to claim 8, characterized in that it is for the treatment of acute hepatitis or cirrhosis of the liver

12. The composition according to claim 8, characterized in that it is for the treatment of rheumatic arthritis.